Radiation therapy (RT) is an effective therapeutic modality in breast cancer used as part of the standard of care to prevent locoregional recurrences and distant metastases. Conventionally, fractionated RT is thought to affect multiple aspects of tumor cell physiology, including the four Rs of radiobiology: repair of DNA damage, redistribution of cells in the cell cycle, repopulation, and reoxygenation. Beyond the four Rs, genetic variation, tumor heterogeneity, and the tumor microenvironment can also contribute to radiosensitivity in breast cancer.1 Although patients with breast cancer are almost always treated with a multimodal approach, the coadministration of available therapies with RT can have a large effect on tumor response by changing the sensitivity of cancer cells to RT and sparing normal tissue. For the treatment of breast cancer in particular, combining RT with other cytotoxic or targeted therapies has led to improvements in recurrence-free and disease-free survival rates. There are several preclinical and clinical approaches to the radiosensitization of aggressive breast cancers, which can have an effect both on current treatment strategies and potential changes to the standard of care.

Context

  • Key Objective

  • Treatment of breast cancer may involve the use of combination therapies that increase the effectiveness of radiation therapy. However, because treatment response can be variable and subtype-dependent, there is a critical need for new therapies that can safely and effectively synergize with radiation to improve patient outcomes.

  • Knowledge Generated

  • While highlighting the historical rationale and present use of current radiosensitization strategies, we review the preclinical rationale and clinical use of novel radiosensitizers. Mechanistically, these combinations potentiate the effects of radiation by targeting immune checkpoints, apoptosis, or hypoxia, among others.

  • Relevance

  • Personalized medicine has not been fully integrated into radiation treatment for breast cancer. There are, however, over 30 open clinical trials examining radiation combination therapies in breast cancer, with an even larger number under preclinical investigation. These studies will determine therapeutic efficacy and the potential for subtype-dependent radiosensitization, which will be important for patient selection in future clinical trials.

Treatment of breast cancer in patients without metastatic spread of disease has always included surgical removal of the tumor. Although surgical resection remains part of the modern treatment paradigm, chemotherapy and radiation therapy have been added to the standard of care in certain patients based on the results of multiple phase III randomized trials demonstrating improved disease-free and overall survival.2,3 Since then, the benefits of chemotherapy in breast cancer have become well established, and many studies have sought to determine the most effective agents and sequence to use in both the neoadjuvant setting and the adjuvant setting.4 Many of these agents work by introducing or potentiating DNA damage, and combination therapy with RT has shown synergy with several chemotherapeutic agents.

Many chemotherapy agents used for the treatment of breast cancer work by inhibiting the synthesis of DNA or its precursors, including fluorinated pyrimidine analogs such as gemcitabine and 5-fluorouracil or the purine nucleoside antimetabolite cordycepin.5 Preclinical studies with gemcitabine showed efficacy as radiosensitizing strategy in both wild-type and p53 mutant MCF-7 cells6 (although initial results from others were mixed),7 and have led to clinical trials with gemcitabine8 and capecitabine9,10 (ClinicalTrials.gov identifier: NCT03958721) in combination with RT. These pivotal studies were some of the first to demonstrate the value of combination chemotherapy and RT in breast cancer, which has led to an increased interest in the potential use of other chemotherapeutic agents with concurrent RT. A similar mechanism occurs with 5-fluorouracil, the active component of the prodrug capecitabine, which leads to G1/S cell cycle reassortment and increased tumor regression when administered to patients with neoadjuvant chemotherapy-refractory, inoperable, advanced breast cancer.11 By interfering with DNA synthesis and DNA repair, nucleoside and nucleotide analogs increase the ability of RT to potentiate lethal double-strand DNA (dsDNA) breaks in breast cancer cells.5-7

Other antineoplastic drug classes that regulate the epigenetic addition or removal of bulky groups from the DNA backbone are also commonly used in the treatment of breast cancer and have recently been shown to influence radiation sensitivity. For example, the enzyme DNA methyltransferase, which adds regulatory methyl groups to DNA, can be inhibited at high concentrations with 5-aza-2′-deoxycytidine in order to radiosensitize triple-negative breast cancer (TNBC) cells by inducing G2/M arrest and stalling DNA repair.12 By contrast, cisplatin and other alkylating agents bind to purine nucleotides in DNA such as guanine and cross-link DNA to prevent proper strand separation necessary for DNA replication.

The safety of cisplatin and RT is being explored in patients with stage II or III TNBC (ClinicalTrials.gov identifier: NCT01674842), but in patients with inflammatory breast cancer, 5-fluorouracil and cisplatin given concurrently with a total dose of 65 Gy fractionated RT has already demonstrated an increase in overall and disease-free survival with minimal associated toxicities compared with convential radiotherapy.13 Clinical use of alkylating agents can result in dose-limiting skin toxicities, but a recent phase I/II clinical trial with cyclophosphamide and the anthracycline doxorubicin (ClinicalTrials.gov identifier: NCT00278109) with partial breast irradiation reported minimal toxicities.14 More targeted studies are also underway to determine the effects of combination therapy specifically for patients with breast cancer brain metastases with RT and temozolomide (ClinicalTrials.gov identifier: NCT00875355, NCT02133677).

Taxanes, such as paclitaxel, work by stabilizing microtubule assembly and are widely used as part of neoadjuvant treatment of breast cancer to shrink tumors before surgical resection; they also remain part of the backbone of standard adjuvant therapy for node-positive or advanced-stage breast cancer. Combination therapy with microtubule-stabilizing agents and RT has been reported to be safe across many different cancer types, and there have been multiple phase II clinical studies in breast cancer that have reported combinations of either docetaxel,15 paclitaxel16 (ClinicalTrials.gov identifier: NCT00006256, NCT00003050), or ixabepilone (ClinicalTrials.gov identifier: NCT01818999) with concurrent RT. Although our understanding of the interactions between cytotoxic chemotherapies and RT are increasing, further studies are needed to pinpoint optimal treatment paradigms and understand the incidence and severity of potential side effects.

Breast cancers are molecularly categorized by the presence of nuclear hormone receptors such as the estrogen receptor (ER), progesterone receptor, and—more recently—the androgen receptor (AR), because these molecular differences lead to large disparities in the effectiveness of targeted and nontargeted treatments. The first molecularly targeted therapy to be approved for breast cancer was tamoxifen, in the 1970s, which acts as a selective ER modulator to antagonize ER signaling in breast tissue. Although effective as a monotherapy, inhibition of nuclear hormone receptor signaling is of increasing interest as a modulator of radiosensitivity in breast cancer.17

Although previously recognized as a therapeutic approach in prostate cancer,18,19 pharmacologic inhibition of AR has been shown to radiosensitize AR+ breast cancer cells.20,21 Mechanistic studies have suggested a role for AR in DNA-dependent protein kinase (DNAPK) signaling and the nonhomologous end joining (NHEJ) response to dsDNA breaks,20 although at present AR's transcriptional ability cannot be excluded as a potential mechanism of radiosensitivity. In addition, inhibition of HSP90, a protein chaperone that interacts with both the androgen and ER, can also modify radiosensitivity of breast cancer cells.22 This may suggest that modulation of multiple types of hormone receptor signaling pathways may be able to affect the cellular response to RT, although HSP90 client proteins are diverse, including other mediators of radiosensitivity such as the DNA damage response protein ATR.23

ER, most commonly exploited with targeted antiestrogen therapies such as tamoxifen in the treatment of ER-positive (ER+) breast cancers, is less understood in terms of its role in the radiation response. Since the approval of the first antiestrogen therapies, the question of whether or not to administer hormone therapy concurrently with RT has remained an important clinical question.17 There is preclinical evidence to suggest that ER itself may be a modulator of radiosensitivity, and that its absence may directly contribute to the intrinsic radioresistance of TNBC cells that do not express ER, progesterone receptor, or human epidermal growth factor receptor 2 (HER2).24 This is also consistent with the clinical observation by Kyndi et al25 that HER2+ and TNBC have higher rates of locoregional recurrence after RT than ER+ patients.25 Furthermore, knockdown or loss of ER expression in ER+ breast cancer cell lines has been associated with radioresistance.26

It is known that the response of ER+, estrogen-dependent breast cancer cell lines to therapies such as tamoxifen and RT is highly dependent on many factors, including the availability of estrogens and the size of the tumor (or spheroid).27 The historical perception of this proposed combination therapy was based on the hypothesis that by stopping or slowing the growth of rapidly proliferating ER+ breast cancer cells with anti-ER therapies, RT would be less effective, as RT is most effective in rapidly cycling cells. Additionally, cells would arrest in G0/G1, the least radiosensitive phase of the cell cycle. Indeed, initial studies with tamoxifen showed that radiosensitivity is influenced by the overall availability of estrogens, suggesting that tamoxifen slightly radioprotects ER+ breast cancer cells.28 Exogenous 17-β-estradiol can be used to blunt this effect,27,28 suggesting that this is a direct effect of estrogenic signaling pathways.

Although these studies suggested some antagonism between inhibition of ER signaling and RT therapy in breast cancer cells, more recent preclinical studies hint that this interaction might be slightly more synergistic than previously thought. Wang et al29 showed that pretreatment of MCF-7 cells with fulvestrant leads to decreased cell survival in combination with RT through suppression of DNA damage response pathways and G1 cell cycle arrest. In line with these findings, tamoxifen treatment of mammary tumors in female Sprague Dawley rats exposed to 1-methyl-1-nitrosourea decreased both the size and metastatic dissemination of tumor cells to a greater degree than either tamoxifen or RT alone.30

These types of translational questions become even more complicated beyond the confines of a controlled, experimental setting, and clinically there is currently no consensus as to the most effective sequence of tamoxifen and RT therapy. Some studies have reported no sequence dependence in preventing locoregional recurrence when combining tamoxifen and RT,31,32 whereas others have suggested a potential benefit of concurrent tamoxifen and RT.33-35 To that end, there are multiple ongoing phase III clinical trials that seek to optimize the timing of endocrine therapies such as tamoxifen (CONSET, ClinicalTrials.gov identifier: NCT00896155) or the aromatase inhibitor anastrozole (STARS, ClinicalTrials.gov identifier: NCT00887380) and RT. More comprehensive phase IV clinical trials such as REaCT-RETT (ClinicalTrials.gov identifier: NCT03948568) are also underway to provide a more complete understanding of additional toxicities or side effects that may result from combination treatment with RT and endocrine therapies.

Along with the presence of nuclear hormone receptors, breast cancers are stratified based on amplification of HER2, which is part of the epidermal growth factor receptor (EGFR) family of receptor tyrosine kinases. HER2 signaling drives growth and proliferation in HER2-amplified breast cancers, but overexpression of the HER2 protein has also been correlated with radioresistance.36,37 With the use of genetic HER2 knockdown37,38 or silica nanoparticles expressing anti-HER2 antibodies39 in HER2-expressing cell lines, this radioresistance phenotype can be reversed. It is also known that HER2-overexpressing breast cancer stem cells express higher levels of aldehyde dehydrogenase and are more radioresistant than their HER2-negative counterparts,38 suggesting that this aggressive and radioresistant subpopulation of cells can contribute to disease relapse or metastasis.

Clinically, HER2 inhibition is an effective monotherapy for patients with HER2-amplified tumors. The monoclonal antibody trastuzumab (Herceptin) was approved in 1998 for patients with HER+ breast cancer as the first (US) Food and Drug Administration–approved monoclonal antibody for a solid tumor. Mechanistically, trastuzumab works by binding to the extracellular portion of HER2 to block HER2-mediated signaling. When trastuzumab is administered with RT, breast cancer cell lines display decreased Akt and mitogen-activated protein kinase/extracellular regulated kinase (MAPK/ERK) phosphorylation and increased apoptosis compared to treatment with trastuzumab alone.40,41 There is also some evidence to suggest that trastuzumab may affect the efficiency of DNA repair pathways and the cell cycle,42 which may contribute to radiosensitization. As a result, the combination of trastuzumab and external beam RT has been evaluated in multiple trials for patients with HER2-overexpressing breast cancer (ClinicalTrials.gov identifier: NCT00943410),43 as well as in patients with HER2+ ductal carcinoma in situ to improve the efficacy of therapy (ClinicalTrials.gov identifier: NCT00769379).

In the years following, the small molecule dual tyrosine kinase inhibitor lapatinib was approved for the treatment of HER2+ breast cancers that progressed after adjuvant chemotherapy or treatment failure with trastuzumab. Unlike trastuzumab, lapatinib binds intracellularly to prohibit HER2 autophosphorylation and dimerization, but the radiosensitizing effects of HER2 inhibition appear to be comparable with both drugs. Preclinical studies with lapatinib have demonstrated similar suppression of AKT/ERK signaling44-46 and decreased phosphorylation of DNAPK, a crucial mediator of NHEJ.44 In addition to unresolved dsDNA breaks, lapatinib + RT causes increased senescence and apoptosis in breast cancer cells.44 Since its approval, lapatinib has also been used clinically (ClinicalTrials.gov identifier: NCT00379509, NCT01868503)43 in combination with RT to radiosensitize HER2+ breast cancers. In addition, targeted clinical trials have been developed to explore whole-brain RT or stereotactic radiosurgery with lapatinib for patients with brain metastases (ClinicalTrials.gov identifier: NCT01622868). Other related anti-HER2 targeting therapies such as pertuzumab and trastuzumab emtansine are routinely used in the treatment of HER2+ breast cancers, but their utility as radiosensitization agents has not been directly studied.

The observation that RT induces phosphorylation of EGFR family members in breast cancer cell lines—beyond just HER2—was one of the first indications that EGFR signaling may influence the radiation response in breast cancer.47,48 In models of breast cancer with acquired resistance to radiation, ER+ breast cancer cell lines such as MCF-7 and ZR-751s lose expression of ER and gain expression of HER2/EGFR signaling,26,48 suggesting that these compensatory growth signaling pathways may be important in the radiation response. Recently published data also suggest that EGFR signaling activity may influence early local recurrences after radiation, further supporting a role for the EGFR signaling pathway in radiation resistance.49 Although it is clear that modulation of HER2/EGFR signaling is an attractive radiosensitization strategy in breast cancer, the extensive repertoire of compounds and strategies available to manipulate this system—including additional EGFR family members and novel compounds that lead to cosuppression of multiple signaling pathways (Appendix)—creates many opportunities to determine the optimal clinical approach.

Numerous studies have elucidated the far-reaching effects of PI3K inhibition, some of which play a role in the radiation response in breast cancer. After exposure to ionizing RT, the resulting activation of PI3K/AKT signaling leads to growth-stimulatory effects that are radioprotective, and these effects can be reversed with the addition of specific PI3K or mammalian target of rapamycin (mTOR) pathway inhibitors.50,51 In addition to mutations, overexpression, and amplification of the PI3K family proteins that are common in breast cancer, cosuppression of PI3K signaling and other pathways that drive proliferation can lead to synergistic responses. In the context of EGFR/HER2-mediated radioresistance, the addition of PI3K inhibition to either EGFR52 or HER2 inhibition53 can lead to synergistic responses that increase cell death through changes in cell cycle distribution or an increase in apoptosis. Pharmacologic PI3K inhibition in combination with RT influences the expression of other pathways, such as NF-κB signaling54 or ERK/MEK signaling,40,46,55 that increase the efficacy of radiation treatment,56 but perhaps the most common cotargeted pathway with PIK3CA inhibition is the mTOR signaling pathway (Appendix).

In contrast to the use of targeted therapies that are unique to the underlying physiology of breast cancer, other radiosensitization strategies are effective across a range of cancer types. Pharmacologic inhibition of polyadenosine ribosome polymerase (PARP), first approved for ovarian cancer, is now being used both as a monotherapy and in combination with RT for the treatment of inflammatory57,58 (ClinicalTrials.gov identifier: NCT03598257) breast cancer and TNBC59 (ClinicalTrials.gov identifier: NCT03109080). Although generally well tolerated during treatment, long-term follow-up revealed significant long-term toxicities that were not initially apparent in preclinical and early clinical data. Despite this, similar studies are underway with newer PARP inhibitors such as rucaparib (ClinicalTrials.gov identifier: NCT03542175) and niraparib60,61 (ClinicalTrials.gov identifier: NCT03945721).

PARP1 inhibition in combination with RT is thought to increase breast cancer cell death by broadly suppressing DNA repair and increasing the number of dsDNA breaks.57,59,62 The PARP protein catalyzes the polymerization of ADP-ribose groups to sites of DNA damage, using ADP donated from a required NAD+ cofactor. Because the nicotinamide precursor needed for PARP1-mediated ribosylation is an endogenous inhibitor of PARP1, NAD+ itself also has the ability to radiosensitize breast cancer cell lines in a PARP-dependent manner.63 The addition of these polymerized groups recruits necessary protein machinery for single-strand DNA repair processes such as base excision repair, nucleotide excision repair, and mismatch repair, as well as dsDNA repair pathways such as homologous recombination (HR) and NHEJ. In breast cancers with existing deficits in DNA repair capacity— such as BRCA1/2 mutations—the addition of a PARP inhibitor leads to suppression of DNA repair and leads to synthetic lethality.57,59

Although PARP inhibitors often take advantage of existing DNA repair deficits, there are numerous ways to suppress DNA repair capacity in breast cancer. Ionizing radiation induces predominantly single-strand breaks in DNA, and it has been shown that mutations in single-strand repair pathways (such as the mismatch repair genes MSH2 and MSH3) may confer radiosensitivity to breast tumors.64 However, it is the failure of DNA repair and the introduction of dsDNA breaks that are eventually lethal to the cell. Unsurprisingly, preexisting mutations in BRCA1 and ATM have been shown to strongly enhance the response of cells to ionizing radiation.65 Accordingly, selective pharmacologic inhibition of double-strand break repair pathways has been explored as an effective way to enhance the response of breast cancer cells to RT.

Breast cancer cells can repair dsDNA breaks with HR, which is mediated through the actions of proteins such as ATR, ATM, and RAD51. The CHK1/2 inhibitor AZD7762 inhibits the ability of cells to undergo HR and—in combination with RT—radiosensitizes breast cancer cell lines66,67 in a p53-dependent manner.66 Similar results are seen with MK8776 and KU-55933, which target CHK1 and ATM, respectively.68,69 Direct inhibition of the downstream mediator RAD51 with miR-15570 or RAD51 siRNA can also achieve similar results, suggesting that HR can be manipulated in a variety of ways to achieve a radiosensitization phenotype.

When cells lack a template chromosome for HR, or if HR is suppressed, dsDNA breaks must be repaired with NHEJ. NHEJ is the most basic form of dsDNA repair, and inhibition of NHEJ can significantly delay or prevent repair of dsDNA breaks. During NHEJ, DNAPK activation at sites of dsDNA breaks leads to the recruitment of accessory proteins such as Ku70/80 that are necessary for active repair. Because NHEJ does not rely on the availability of template DNA for repair, the resulting repair is more error-prone. Thus, small-molecule DNAPK inhibitors such as NU7761 and AZD7648 sensitize breast cancer cell lines to the toxic effects of RT through the buildup of unresolved dsDNA breaks.69,71,72 Many nonspecific inhibitors of the PI3K kinase family, such as NU744161 or the novel compound PI-103,73 not only inhibit cellular proliferation through inhibition of PI3K, but also retain high affinity for the conserved active site of the PI3K-related kinases DNAPK, ATM, and/or ATR that leads to radiosensitization.

Although many of these preclinical agents are not candidates for further clinical development, inhibition of ATR, which is required for HR initiation, has shown success in the radiosensitization of TNBC cells in the preclinical23,74 and clinical settings. This has led to initial phase I studies to determine the safety of combination therapy with the ATR kinase inhibitor berzosertib (M6620) for TNBC or ER+/HER2− breast cancers (ClinicalTrials.gov identifier: NCT04052555). Berzosertib is also being studied in multiple solid tumor types with preexisting deficits in DNA damage repair (ClinicalTrials.gov identifier: NCT04266912) in combination with RT and the DNAPK inhibitor nedisertib (M3814),75 which has entered early phase I and II clinical trials for the treatment of multiple solid tumor types in combination with RT both with and without the immunomodulatory agent avelumab (ClinicalTrials.gov identifier: NCT04266912, NCT02516813, NCT03724890, and NCT04068194).

The ability of cells to repair damaged DNA is linked inextricably to the control of cell-cycle checkpoints designed to prevent cells from dividing in the presence of DNA damage. Although there are multiple different types of DNA repair, the availability of specific repair proteins and template DNA varies throughout the cell cycle. For example, HR-mediated DNA repair is restricted to the S and G2 phases after DNA has undergone duplication and a sister chromatid is available. Thus, because DNA synthesis and repair are essential to cellular homeostasis and regulated cell division, kinases involved in cell-cycle checkpoints are uniquely positioned to affect the RT response in breast cancer (Appendix).

Immunotherapy plays an increasingly important role in the treatment of advanced, metastatic breast cancer and is likely to have an expanded role in the treatment of patients without metastatic disease, particularly in the case of TNBC.76 Although many studies have examined the addition of immunotherapies to the current standard of care, the novelty of these therapies limits our knowledge of how these novel immune checkpoint inhibitors may influence the response of breast tumors to ionizing radiation. RT is thought to enhance the response of tumors to immunotherapy at least in part through the actions of tumor-associated T cells, such as induction of the DNA exonuclease Trex177 that modulates radiation-induced T-cell regulation in combination with immune checkpoint inhibition.

However, the immunotherapy agents that have shown the most promise in breast cancer so far are undoubtedly the targeted programmed cell death (PD)-1/PD-L1 therapies. In breast cancer cell lines, RT synergizes with anti–PD-1/PD-L1 therapy and enhances tumor kill when given in combination with α-CD137 and α-PD-1 monoclonal antibodies.78 This combination therapy also increases the number of tumor-specific effector immune cells present in the tumors,79 which is thought to contribute to the curative responses seen in vivo. The addition of therapies that block PD-1/PD-L1 signaling has even been shown to overcome acquired resistance to fractionated RT in TNBC and other solid tumors.80 Ongoing clinical trials with RT and PD-1/PD-L1 inhibition are summarized in Table 1. Direct modulation of the PD-1 and PD-L1 interaction also has implications for cytokine and chemokine signaling pathways that modulate the immune response. To that end, anti–transforming growth factor-β therapy has been explored both preclinically81,82 and clinically (ClinicalTrials.gov identifier: NCT01401062 and NCT02538471) (Figs 1-2).

Table

TABLE 1. Current Clinical Trials Assessing the Safety and/or Efficacy of Combination Therapies With Radiation in Women With BC

Although immunotherapies targeting PD-1/PD-L1 or CLTA4 are the most well studied, there are several other therapies that seek to use the immune system to increase the efficacy of RT. Therapies targeted against CTLA4 or toll-like receptors have also shown promise in breast cancer. The abscopal effect has been observed previously in models of breast cancer, and it has been suggested that the immune signaling may be responsible.83 In TSA breast carcinoma cells, mice treated with the CTLA-4 monoclonal antibody 9H10 and radiation showed a decrease not only in the growth of tumors within the radiation field, but an abscopal effect that decreased metastatic growth and resulted in less overall tumor burden in these mice.84 As a result, there are multiple trials examining the anti CTLA4 antibody tremelimumab (ClinicalTrials.gov identifier: NCT02563925 and NCT01334099) in breast cancer.

Immunotherapies that inhibit toll-like receptor signaling in breast cancer (ClinicalTrials.gov identifier: NCT01421017 and NCT03915678) or activate OX40 on the surface of T-cells (ClinicalTrials.gov identifier: NCT01862900) have also been initiated. For breast tumors that do not initially respond to combined immunotherapy and radiation treatment, the addition of Axl inhibition in Axl-expressing tumors increases the efficacy of combination treatment.85 Finally, the immunosuppressant agent fingolimod (FTY720), a sphingosine analog, increases radiosensitivity of breast cancer cells in vitro by inhibiting SphK1 and increasing apoptosis and autophagy.86 In short, immunotherapy will be a prominent feature of current and future radiosensitization studies in breast cancer. Additional detailed descriptions of the immune regulation and infiltration of breast tumors, and the potential side effects and biomarkers for immunotherapy and RT beyond the scope of this paper have recently been reviewed elsewhere.87,88

In conclusion, there are numerous biological pathways that can be manipulated to increase the efficacy of targeted RT for the treatment of breast cancer. Although inhibition of hormone receptors, DNA damage repair, and immunomodulatory signaling represent the majority of the approaches to radiosensitization currently being studied in the clinic (Table 1), there are a number of other emerging preclinical radiosensitization strategies (Table 2, Appendix) and radioprotective approaches to minimize normal tissue toxicity (Appendix). Although not reviewed here, multicandidate approaches to radiosensitization—such as the development of predictive gene signatures—are an important component of future radiosensitization studies because they are able to incorporate gene and protein expression data across multiple pathways alongside data on clinical progression and outcomes. Because many of the signaling pathways involved in the RT response have significant biological overlap, new combination therapies designed for radiosensitization of breast cancer may have the potential to influence the response of the tumor to other modalities used during subsequent treatments. Finally, as novel radiosensitization strategies make their way into the clinic, trials must be designed with appropriate long-term follow-up because combination therapies with RT can often lead to delayed toxicities.

Table

TABLE 2. Novel Preclinical Approaches to Modulate the Radiation Response in Breast Cancer

© 2021 by American Society of Clinical Oncology

Conception and design: All authors

Collection and assembly of data: All authors

Data analysis and interpretation: All authors

Manuscript writing: All authors

Final approval of manuscript: All authors

Accountable for all aspects of the work: All authors

The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated unless otherwise noted. Relationships are self-held unless noted. I = Immediate Family Member, Inst = My Institution. Relationships may not relate to the subject matter of this manuscript. For more information about ASCO's conflict of interest policy, please refer to www.asco.org/rwc or ascopubs.org/po/author-center.

Open Payments is a public database containing information reported by companies about payments made to US-licensed physicians (Open Payments).

Lori J. Pierce

Stock and Other Ownership Interests: PFS Genomics

Patents, Royalties, Other Intellectual Property: UpToDate, PFS Genomics

(OPTIONAL) Uncompensated Relationships: Bristol-Myers Squibb, https://openpaymentsdata.cms.gov/physician/1250431/summary

Corey W. Speers

Stock and Other Ownership Interests: PFS Genomics

Patents, Royalties, Other Intellectual Property: Compositions and Methods for the Analysis of Radiosensitivity, UM-33550/US-1, Coinventor, Submitted on 09/2013, Methods and Genomic Classifiers for Prognosis of Breast Cancer and Predicting Benefit from Adjuvant Radiotherapy, Application No. 61/205,279, Co-inventor

(OPTIONAL) Uncompensated Relationships: PFS Genomics

No other potential conflicts of interest were reported.

Epidermal Growth Factor Receptor and Human Epidermal Growth Factor Receptor 2

Many of the targeted human epidermal growth factor receptor 2 (HER2)/epidermal growth factor receptor (EGFR) inhibitors have some activity across the EGFR family of proteins. However, as EGFR inhibition has become a more relevant treatment strategy in other cancers, newer and more specific EGFR inhibitors such as cetuximab, canertinib, panitumumab, and nimotuzumab have become available, with similar preclinical radiosensitizing effects in breast cancer.89-92 Consistent with existing data for HER2 and EGFR signaling, EGFR3-mediated signaling is radioprotective in breast cancer cells,93,94 but because of the overlap between EGFR signaling pathway signaling, further comparative studies are needed to make direct conclusions comparing the efficacy of specific inhibition of each of the EGFR family members. Furthermore, overexpression of the dominant-negative, truncated EGFR-CD533 protein leads to radiosensitization of breast cancer cells after repeated doses of radiation therapy (RT),95,96 whereas overexpression of TOB1, a negative regulator of HER2 activity, is radiosensitizing.

Although current clinical trials use (US) Food and Drug Administration–approved agents, additional preclinical strategies with novel agents for EGFR/HER2-mediated radiosensitization are also being explored in breast cancer.97-99 Novel inhibitors with activity against insulin-like growth factor receptors have shown efficacy by decreasing pERK signaling in addition to a decrease in p-EGFR,100,101 consistent with the clinical observation that the insulin-like growth factor receptor (IGFR) overexpression after radiation treatment is associated with early local recurrence.102 Additional work has explored the role of small oligonucleotides, such as miR-200c103 and miR-7,104 that deactivate EGFR and upregulate DNA damage signaling pathways, resulting in an increase in γH2AX foci formation and persistence of DNA damage in triple-negative MDA-MB-468 cells. In addition to more effective ways to target HER2/EGFR proteins, HER2-mediated radioresistance can be overcome by targeting compensatory signaling pathways using the small molecular focal adhesion kinase (FAK) inhibitor PF-56228137 or inhibition of downstream NF-κB signaling.36,105

PIK3CA and Mammalian Target of Rapamycin Signaling

The PI3K pathway signaling influences a variety of widespread and interconnected signaling pathways. The PI3K/mammalian target of rapamycin (mTOR) signaling pathway is activated by extracellular receptor tyrosine kinase activity and external signals of cellular stress, including those induced by RT. In the context of breast cancer, the expansion of radioresistant breast cancer stem cell populations and their self-renewal has been attributed to PI3K/mTOR signaling and can be repressed with the combination of RT and dual PI3K/mTOR signaling.106 Dual strategies that target both pathways—or novel compounds such as the novel PI3K/mTOR inhibitor NVP-BEZ235 that block both pathways—have been successful in radiosensitizing breast cancer through suppression of Hypoxia-inducible factor 1-alpha (HIF-1α) signaling as well as increased autophagy and apoptosis.107 Response to RT therapy is also influenced by intact PTEN signaling,108,109 the presence of constitutively active Ras protein,50,110 or modulation of the downstream RAC1 GTPase-involved ERK1/2-mediated G2/M checkpoint activation.111

Many signaling pathways involved in metabolic stress are coordinated through the activation of the mTOR and are closely linked to both the cellular control of autophagy and the radiation response.51,112 Although there are conflicting reports on the ability of the mTORC1 inhibitor rapamycin to radiosensitize breast cancer cell lines,51,106,113 there are a number of studies that demonstrate radiosensitivity through modulation of mTOR pathway members. For example, pharmacologic114,115 or genetic inhibition116 of SIRT1, a negative regulator of mTOR1 function, increases radiosensitivity of breast cancer cells and suppress tumor growth in an interleukin-6–dependent manner. Taken together, these studies indicate a strong potential for PI3K/mTOR family inhibitors, either alone or in combination, to serve as effective radiosenstization agents in the treatment of breast cancer.

Cell Cycle

Cyclin proteins interact with cyclin-dependent kinases (CDKs) to initiate a series of phosphorylation events that drive cells through specific cell-cycle phases and checkpoints. However, pharmacologic inhibition of CDKs can prevent the formation of these critical complexes. Pan-CDK inhibitors such as roscovitine have limited use as monotherapies in breast cancer because of dose-limiting toxicities, but roscovitine in combination with RT may be able to radiosensitize breast cancer cell lines through a suppression of the DNA damage response in p53-mutant cell lines.117,118 With the introduction of more specific CDK inhibitors, more targeted radiosensitization has become possible. The CDK12/13-specific compound SR-4835 radiosensitizes triple-negative breast cancer (TNBC) through a novel mechanism related to the induction of intronic polyadenylation cleavage sites,119 whereas CDK4/6 inhibitors radiosensitive-positive estrogen receptor breast cancers through homologous recombination (HR) suppression.120

Cell-cycle progression is also influenced by tumor-suppressor proteins such as p53 and RB that are often mutated in breast cancer, leading to unchecked cell-cycle progression and variable response to RT. In TNBC cells where the RB protein is frequently mutated or lost, RB1-null cells are more sensitive to γ-irradiation than RB1-intact cell lines.121 Failure to progress through the G1/S cell cycle checkpoint is also complicated by impaired p53 signaling62,66,122,123 or alternations in the p53-specific E3 ubiquitin ligase MDM2 that lead to loss of MDM2-mediated p53 suppression. In HER2-overexpressing breast cancer cell lines, for example, the radiation response is correlated with decreased MDM2 expression,42 consistent with other studies that have reported radiosensitizing effects of anti-MDM2 oligonucleotides,124,125 although this effect occurred regardless of p53 status. Additional tumor suppressor proteins such as BTG1 and BTG2 can also influence breast cancer cell radiosensitivity through pleiotropic effects on cell cycle progression, DNA damage, and apoptosis.126,127

In addition, the actions of other cell-cycle kinases can influence the response to radiation. Although the effects of single-agent inhibition of the cell-cycle kinase maternal embryonic leucine zipper kinase (MELK) on the proliferation of breast cancer cells are debated, it is known that the increase of MELK expression in G2/M is radioprotective in TNBC cells.128 The G2 checkpoint kinase WEE1, which phosphorylates many CDKs necessary for G2 checkpoint progression, can be effectively inhibited with MK-1775 (adavosertib), which is effective as both a single agent and a radiosensitizer in p53-defective models of breast cancer.129 Alternatively, during S phase, the S-phase kinase-associated protein 2 (SKP2) has been suggested to radiosensitize breast cancer through suppression of PDCD4 ubiquitination with either SKP2 knockdown or use of the small-molecule SKP2 inhibitor SMIP004.130

When cells undergo mitosis, proteins of the spindle assembly complex are required for proper cell division and the prevention of aberrant chromosome segregation. This spindle assembly can be targeted directly through MiR-27a–based suppression of CDC27 activity that leads to radiosensitivity,131 or through the inhibition of protein kinases necessary for activation of the spindle assembly complex or anaphase promoting complex. For example, inhibition of MPS1 sensitizes TNBC cell lines through inhibition of HR.132 Similarly, modulation of PP2A, the phosphatase involved in inactivation of MPS1, can also influence the response of positive estrogen receptor breast cancer cells to ionizing radiation.133 Polo-like kinase 1, essential for phosphorylation and activation of the anaphase promoting complex (APC), suppresses cell-cycle progression and the 53BP1-mediated DNA damage response in HR,134 leading to increased breast cancer cell death when combined with ionizing radiation.135 By targeting breast cancer cells in a radiosensitive phase of the cell cycle (predominately G2/M), these strategies lead to more effective tumor cell death in combination with RT.

Emerging Preclinical Strategies

Although many radiosenstization agents have been clinically used for the treatment of breast cancer, there are several radiosensitization strategies that are still under early preclinical investigation (summarized in Table 2). Although many of these strategies target apoptosis,136-148 autophagy in,149-156 or metabolic changes157,158 usually thought to be minor contributing pathways to breast cancer radiosensitization, a number of these approaches likely have mixed mechanisms that lead to broad suppression of the DNA damage response, cell-cycle progression, or decreased hypoxia and HIF1a-related signaling.127,159-167 On-target and off-target effects of compounds designed to affect proliferation or cell-cell communication, such as the suppression of notch signaling168 through gamma secretase inhibition169 (ClinicalTrials.gov identifier: NCT01217411), can also be valuable approaches in the radiosensitization of breast cancer. Finally, the radiosensitizing effects of many natural products and dietary supplements are just starting to be realized,118,170-176 and the concomitant use of these compounds during radiation treatment should be advised with caution in the absence of additional information.

Clinical Strategies for Radioprotection

In addition to emerging clinical strategies to reoxygenate and radiosensitize breast tumors (ClinicalTrials.gov identifier: NCT00083304 with efaproxiral, NCT02757651, NCT03946202 with hydrogen peroxide), there is also an interest in the off-label use of common compounds or pharmaceuticals that may improve the therapeutic index of RT by offering radioprotection of normal tissue. Although terminated, a trial with the popular cholesterol-lowering statin lovastatin was initiated to study the potential of concurrent statin treatment to ameliorate long-term effects of RT (ClinicalTrials.gov identifier: NCT00902668). Even the sleep-aid melatonin, taken primarily to improve duration and quality of sleep, has mixed effects on radiation sensitivity, and has been proposed as an adjunct therapy to decrease radiation-induced dermatitis in breast cancer (ClinicalTrials.gov identifier: NCT03716583). Topical radioprotection has been explored using curcumin (ClinicalTrials.gov identifier: NCT01042938), the anti-inflammatory compound found in turmeric, or the tricyclic antidepressant doxepin (ClinicalTrials.gov identifier: NCT02447211) to prevent the formation of skin lesions. Finally, the vasodilatory compound pentoxifylline has also been used clinically and has been shown to prevent radiation-induced fibrosis in patients with breast cancer receiving multimodal treatment.177-179 Although still under investigation, strategies to mitigate side effects from radiation or minimize healthy tissue toxicity provide unique insight into the radiation response in both tumor and healthy tissues.

ACKNOWLEDGMENT

The authors would like to acknowledge funding support from the NIH Pharmacological Sciences Training Program (T32GM007767 to AP), the National Cancer Institute of the National Institutes of Health (F31CA254138 to AP), and the University of Michigan Center for the Education of Women+ (Irma M. Wyman Fellowship to AP). The authors would also like to thank BioRender for assistance in making all figures.

1. Yard BD, Adams DJ, Chie EK, et al: A genetic basis for the variation in the vulnerability of cancer to DNA damage. Nat Commun 7:11428, 2016 Crossref, MedlineGoogle Scholar
2. Early Breast Cancer Trialists' Collaborative Group (EBCTCG), Peto R, Davies C, Godwin J, et al: Comparisons between different polychemotherapy regimens for early breast cancer: Meta-analyses of long-term outcome among 100,000 women in 123 randomised trials. Lancet 379: 432-444, 2012 Crossref, MedlineGoogle Scholar
3. Early Breast Cancer Trialists' Collaborative Group (EBCTCG), Darby S, McGaleP, CorreaC, et al: Effect of radiotherapy after breast-conserving surgery on 10-year recurrence and 15-year breast cancer death: Meta-analysis of individual patient data for 10,801 women in 17 randomised trials. Lancet 378:1707-1716, 2011 Crossref, MedlineGoogle Scholar
4. EBCTCG (Early Breast Cancer Trialists' Collaborative Group)
McGale P, Taylor C, Correa C, et al: Effect of radiotherapy after mastectomy and axillary surgery on 10-year recurrence and 20-year breast cancer mortality: Meta-analysis of individual patient data for 8135 women in 22 randomised trials. Lancet 383:2127-2135, 2014 Crossref, MedlineGoogle ScholarGoogle Scholar
5. Dong J, Li Y, Xiao H, et al: Cordycepin sensitizes breast cancer cells toward irradiation through elevating ROS production involving Nrf2. Toxicol Appl Pharmacol 364:12-21, 2019 Crossref, MedlineGoogle Scholar
6. Robinson BW, Shewach DS: Radiosensitization by gemcitabine in p53 wild-type and mutant MCF-7 breast carcinoma cell lines. Clin Cancer Res 7:2581-2589, 2001 MedlineGoogle Scholar
7. Salem SD, Abou-Tarboush FM, Saeed NM, et al: Involvement of p53 in gemcitabine mediated cytotoxicity and radiosensitivity in breast cancer cell lines. Gene 498:300-307, 2012 Crossref, MedlineGoogle Scholar
8. Suh WW, Schott AF, HaymanJA, et al: A phase I dose escalation trial of gemcitabine with radiotherapy for breast cancer in the treatment of unresectable chest wall recurrences. Breast J 10:204-210, 2004 Crossref, MedlineGoogle Scholar
9. Liu YL, Chin C, Catanese B, et al: Concurrent use of capecitabine with radiation therapy and survival in breast cancer (BC) after neoadjuvant chemotherapy. Clin Transl Oncol 20:1280-1288, 2018 Crossref, MedlineGoogle Scholar
10. Gaui MF, Amorim G, Arcuri RA, et al: A phase II study of second-line neoadjuvant chemotherapy with capecitabine and radiation therapy for anthracycline-resistant locally advanced breast cancer. Am J Clin Oncol 30:78-81, 2007 Crossref, MedlineGoogle Scholar
11. Bourgier C, Ghorbel I, Heymann S, et al: Effect of preoperative rescue concomitant FUN/XUN-based chemo-radiotherapy for neoadjuvant chemotherapy-refractory breast cancer. Radiother Oncol 103:151-154, 2012 Crossref, MedlineGoogle Scholar
12. Wang L, Zhang Y, Li R, et al: 5-aza-2′-Deoxycytidine enhances the radiosensitivity of breast cancer cells. Cancer Biother Radiopharm 28:34-44, 2013 Crossref, MedlineGoogle Scholar
13. Genet D, Lejeune C, Bonnier P, et al: Concomitant intensive chemoradiotherapy induction in non-metastatic inflammatory breast cancer: Long-term follow-up. Br J Cancer 97:883-887, 2007 Crossref, MedlineGoogle Scholar
14. Zellars RC, Frassica D, Stearns V, et al: Phase I/II trial of partial breast irradiation with concurrent dose-dense doxorubicin and cyclophosphamide (ddAC) chemotherapy in early stage breast cancer: Report of skin toxicity and cosmetic outcome. Int J Radiat Oncol Biol Phys 69, 2007 CrossrefGoogle Scholar
15. Brackstone M, Palma D, Tuck AB, et al: Concurrent neoadjuvant chemotherapy and radiation therapy in locally advanced breast cancer. Int J Radiat Oncol Biol Phys 99:769-776, 2017 Crossref, MedlineGoogle Scholar
16. Adams S, Chakravarthy AB, Donach M, et al: Preoperative concurrent paclitaxel-radiation in locally advanced breast cancer: Pathologic response correlates with five-year overall survival. Breast Cancer Res Treat 124:723-732, 2010 Crossref, MedlineGoogle Scholar
17. Chargari C, Toillon RA, Macdermed D, et al: Concurrent hormone and radiation therapy in patients with breast cancer: What is the rationale? Lancet Oncol 10:53-60, 2009 Crossref, MedlineGoogle Scholar
18. Polkinghorn WR, Parker JS, Lee MX, et al: Androgen receptor signaling regulates DNA repair in prostate cancers. Cancer Discov 3:1245-1253, 2013 Crossref, MedlineGoogle Scholar
19. Goodwin JF, Schiewer MJ, Dean JL, et al: A hormone-DNA repair circuit governs the response to genotoxic insult. Cancer Discov 3:1254-1271, 2013 Crossref, MedlineGoogle Scholar
20. Speers C, Zhao SG, Chandler B, et al: Androgen receptor as a mediator and biomarker of radioresistance in triple-negative breast cancer. NPJ Breast Cancer 3:29, 2017 Crossref, MedlineGoogle Scholar
21. Michmerhuizen AR, Chandler B, Olsen E, et al: Seviteronel, a novel CYP17 lyase inhibitor and androgen receptor antagonist, radiosensitizes AR-positive triple negative breast cancer cells. Front Endocrinol (Lausanne) 11:35, 2020 Crossref, MedlineGoogle Scholar
22. Kale S, Korcum AF, Dundar E, et al: HSP90 inhibitor PU-H71 increases radiosensitivity of breast cancer cells metastasized to visceral organs and alters the levels of inflammatory mediators. Naunyn Schmiedebergs Arch Pharmacol 393:253-262, 2020 Crossref, MedlineGoogle Scholar
23. Ha K, Fiskus W, Rao R, et al: HSP90 inhibitor-mediated disruption of chaperone association of ATR with HSP90 sensitizes cancer cells to DNA damage. Mol Cancer Ther 10:1194-1206, 2011 Crossref, MedlineGoogle Scholar
24. Chen X, Ma N, Zhou Z, et al: Estrogen receptor mediates the radiosensitivity of triple-negative breast cancer cells. Med Sci Monit 23:2674-2683, 2017 Crossref, MedlineGoogle Scholar
25. Kyndi M, Sørensen FB, Knudsen H, et al: Estrogen receptor, progesterone receptor, HER-2, and response to postmastectomy radiotherapy in high-risk breast cancer: The Danish breast cancer cooperative group. J Clin Oncol 26:1419-1426, 2008 LinkGoogle Scholar
26. Gray M, Turnbull AK, Ward C, et al: Development and characterisation of acquired radioresistant breast cancer cell lines. Radiat Oncol 14:64, 2019 Crossref, MedlineGoogle Scholar
27. Villalobos M, Aranda M, Nuñez MI, et al: Interaction between ionizing radiation, estrogens and antiestrogens in the modification of tumor microenvironment in estrogen dependent multicellular spheroids. Acta Oncol 34:413-417, 1995 Crossref, MedlineGoogle Scholar
28. Wazer DE, Tercilla OF, Lin PS, et al: Modulation in the radiosensitivity of MCF-7 human breast carcinoma cells by 17B-estradiol and tamoxifen. Br J Radiol 62:1079-1083, 1989 Crossref, MedlineGoogle Scholar
29. Wang J, Yang Q, Haffty BG, et al: Fulvestrant radiosensitizes human estrogen receptor-positive breast cancer cells. Biochem Biophys Res Commun 431:146-151, 2013 Crossref, MedlineGoogle Scholar
30. Kantorowitz DA, Thompson HJ, Furmanski P: Effect of conjoint administration of tamoxifen and high-dose radiation on the development of mammary carcinoma. Int J Radiat Oncol Biol Phys 26:89-94, 1993 Crossref, MedlineGoogle Scholar
31. Pierce LJ, Hutchins LF, Green SR, et al: Sequencing of tamoxifen and radiotherapy after breast-conserving surgery in early-stage breast cancer. J Clin Oncol 23:24-29, 2005 LinkGoogle Scholar
32. Ahn PH, Vu HT, Lannin D, et al: Sequence of radiotherapy with tamoxifen in conservatively managed breast cancer does not affect local relapse rates. J Clin Oncol 23:17-23, 2005 LinkGoogle Scholar
33. Dalberg K, Johansson H, Johansson U, et al: A randomized trial of long term adjuvant tamoxifen plus postoperative radiation therapy versus radiation therapy alone for patients with early stage breast carcinoma treated with breast-conserving surgery. Stockholm Breast Cancer Study Group. Cancer 82:2204-2211, 1998 Crossref, MedlineGoogle Scholar
34. Fisher B, Bryant J, Dignam JJ, et al: Tamoxifen, radiation therapy, or both for prevention of ipsilateral breast tumor recurrence after lumpectomy in women with invasive breast cancers of one centimeter or less. J Clin Oncol 20:4141-4149, 2002 LinkGoogle Scholar
35. Fyles AW, McCready DR, Manchul LA, et al: Tamoxifen with or without breast irradiation in women 50 years of age or older with early breast cancer. N Engl J Med 351:963-970, 2004 Crossref, MedlineGoogle Scholar
36. Guo G, Wang T, Gao Q, et al: Expression of ErbB2 enhances radiation-induced NF-kappaB activation. Oncogene 23:535-545, 2004 Crossref, MedlineGoogle Scholar
37. Hou J, Zhou Z, Chen X, et al: HER2 reduces breast cancer radiosensitivity by activating focal adhesion kinase in vitro and in vivo. Oncotarget 7:45186-45198, 2016 Crossref, MedlineGoogle Scholar
38. Duru N, Fan M, Candas D, et al: HER2-associated radioresistance of breast cancer stem cells isolated from HER2-negative breast cancer cells. Clin Cancer Res 18:6634-6647, 2012 Crossref, MedlineGoogle Scholar
39. Yamaguchi H, Hayama K, Sasagawa I, et al: HER2-targeted multifunctional silica nanoparticles specifically enhance the radiosensitivity of HER2-overexpressing breast cancer cells. Int J Mol Sci 19:908, 2018 CrossrefGoogle Scholar
40. Liang K, Lu Y, Jin W, et al: Sensitization of breast cancer cells to radiation by trastuzumab. Mol Cancer Ther 2:1113-1120, 2003 MedlineGoogle Scholar
41. Samani RK, Tavakolia MB, Maghsoudinia F, et al: Trastuzumab and folic acid functionalized gold nanoclusters as a dual-targeted radiosensitizer for megavoltage radiation therapy of human breast cancer. Eur J Pharm Sci 153:105487, 2020 Crossref, MedlineGoogle Scholar
42. Pietras RJ, Poen JC, Gallardo D, et al; Monoclonal antibody to HER-2/neureceptor modulates repair of radiation-induced DNA damage and enhances radiosensitivity of human breast cancer cells overexpressing this oncogene. Cancer Res 59:1347-1355, 1999 MedlineGoogle Scholar
43. Horton JK, Halle J, Ferraro M, et al: Radiosensitization of chemotherapy-refractory, locally advanced or locally recurrent breast cancer with trastuzumab: A phase II trial. Int J Radiat Oncol Biol Phys 76:998-1004, 2010 Crossref, MedlineGoogle Scholar
44. Yu T, Cho BJ, Choi EJ, et al: Radiosensitizing effect of lapatinib in human epidermal growth factor receptor 2-positive breast cancer cells. Oncotarget 7:79089-79100, 2016 Crossref, MedlineGoogle Scholar
45. Sambade MJ, Kimple RJ, Camp JT, et al: Lapatinib in combination with radiation diminishes tumor regrowth in HER2+ and basal-like/EGFR+ breast tumor xenografts. Int J Radiat Oncol Biol Phys 77:575-581, 2010 Crossref, MedlineGoogle Scholar
46. Sambade MJ, Camp JT, Kimple RJ, et al: Mechanism of lapatinib-mediated radiosensitization of breast cancer cells is primarily by inhibition of the Raf>MEK>ERK mitogen-activated protein kinase cascade and radiosensitization of lapatinib-resistant cells restored by direct inhibition of MEK. Radiother Oncol 93:639-644, 2009 Crossref, MedlineGoogle Scholar
47. Schmidt-Ullrich RK, Valerie K, Fogleman PB, et al: Radiation-induced autophosphorylation of epidermal growth factor receptor in human malignant mammary and squamous epithelial cells. Radiat Res 145:81-85, 1996 Crossref, MedlineGoogle Scholar
48. Schmidt-Ullrich RK, Valerie KC, Chan W, et al: Altered expression of epidermal growth factor receptor and estrogen receptor in MCF-7 cells after single and repeated radiation exposures. Int J Radiat Oncol Biol Phys 29:813-819, 1994 Crossref, MedlineGoogle Scholar
49. Speers C, Chang SL, Pesch A, et al: A signature that may Be predictive of early vs late recurrence after radiation treatment (RT) for breast cancer that may inform the biology of early, aggressive recurrences. Int J Radiat Oncol Biol Phys 108:686-696, 2020 Crossref, MedlineGoogle Scholar
50. Liang K, Jin W, Knuefermann C, et al: Targeting the phosphatidylinositol 3-kinase/Akt pathway for enhancing breast cancer cells to radiotherapy. Mol Cancer Ther 2:353-360, 2003 MedlineGoogle Scholar
51. Holler M, Grottke A, Mueck K, et al: Dual targeting of Akt and mTORC1 impairs repair of DNA double-strand breaks and increases radiation sensitivity of human tumor cells. PLoS One 11:e0154745, 2016 Crossref, MedlineGoogle Scholar
52. Li P, Zhang Q, Torossian A, et al: Simultaneous inhibition of EGFR and PI3K enhances radiosensitivity in human breast cancer. Int J Radiat Oncol Biol Phys 83:e391-e397, 2012 Crossref, MedlineGoogle Scholar
53. No M, Choi EJ, Kim IA: Targeting HER2 signaling pathway for radiosensitization: Alternative strategy for therapeutic resistance. Cancer Biol Ther 8:2351-2361, 2009 Crossref, MedlineGoogle Scholar
54. Andrade D, Mehta M, Griffith JF, et al: YAP1 inhibition radiosensitizes triple negative breast cancer cells by targeting the DNA damage response and cell survival pathways. Oncotarget 8:98495-98508, 2017 Crossref, MedlineGoogle Scholar
55. Hu T, Zhou R, Zhao Y, et al: Integrin alpha6/Akt/Erk signaling is essential for human breast cancer resistance to radiotherapy. Sci Rep 6:33376, 2016 Crossref, MedlineGoogle Scholar
56. Wang T, Hu YC, Dong S, et al: Co-activation of ERK, NF-kappaB, and GADD45beta in response to ionizing radiation. J Biol Chem 280:12593-12601, 2005 Crossref, MedlineGoogle Scholar
57. Michmerhuizen AR, Pesch AM, Moubadder L, et al: PARP1 inhibition radiosensitizes models of inflammatory breast cancer to ionizing radiation. Mol Cancer Ther 18:2063-2073, 2019 Crossref, MedlineGoogle Scholar
58. Jagsi R, Griffith KA, Bellon JR, et al: TBCRC 024 initial results: A multicenter phase 1 study of veliparib administered concurrently with chest wall and nodal radiation therapy in patients with inflammatory or locoregionally recurrent breast cancer. Int J Radiat Oncol 93:S137, 2015 CrossrefGoogle Scholar
59. Feng FY, Speers C, Liu M, et al: Targeted radiosensitization with PARP1 inhibition: Optimization of therapy and identification of biomarkers of response in breast cancer. Breast Cancer Res Treat 147:81-94, 2014 Crossref, MedlineGoogle Scholar
60. Bridges KA, Toniatti C, Buser CA, et al: Niraparib (MK-4827), a novel poly(ADP-ribose) polymerase inhibitor, radiosensitizes human lung and breast cancer cells. Oncotarget 5:5076-5086, 2014 Crossref, MedlineGoogle Scholar
61. Wang L, Mason KA, Ang KK, et al: MK-4827, a PARP-1/-2 inhibitor, strongly enhances response of human lung and breast cancer xenografts to radiation. Invest New Drugs 30:2113-2120, 2012 Crossref, MedlineGoogle Scholar
62. Sizemore ST, Mohammad R, Sizemore GM, et al: Synthetic lethality of PARP inhibition and ionizing radiation is p53-dependent. Mol Cancer Res 16:1092-1102, 2018 Crossref, MedlineGoogle Scholar
63. Dominguez-Gomez G, Díaz-Chávez J, Chávez-Blanco A, et al: Nicotinamide sensitizes human breast cancer cells to the cytotoxic effects of radiation and cisplatin. Oncol Rep 33:721-728, 2015 Crossref, MedlineGoogle Scholar
64. Mangoni M, Bisanzi S, Carozzi F, et al: Association between genetic polymorphisms in the XRCC1, XRCC3, XPD, GSTM1, GSTT1, MSH2, MLH1, MSH3, and MGMT genes and radiosensitivity in breast cancer patients. Int J Radiat Oncol Biol Phys 81:52-58, 2011 Crossref, MedlineGoogle Scholar
65. Mamon HJ, Dahlberg W, Azzam EI, et al: Differing effects of breast cancer 1, early onset (BRCA1) and ataxia-telangiectasia mutated (ATM) mutations on cellular responses to ionizing radiation. Int J Radiat Biol 79:817-829, 2003 Crossref, MedlineGoogle Scholar
66. Ma Z, Yao G, Zhou B, et al: The Chk1 inhibitor AZD7762 sensitises p53 mutant breast cancer cells to radiation in vitro and in vivo. Mol Med Rep 6:897-903, 2012 Crossref, MedlineGoogle Scholar
67. Zhang Y, Lai J, Du Z, et al: Targeting radioresistant breast cancer cells by single agent CHK1 inhibitor via enhancing replication stress. Oncotarget 7:34688-34702, 2016 Crossref, MedlineGoogle Scholar
68. Zhou Z, Yang ZZ, Wang SJ, et al: The Chk1 inhibitor MK-8776 increases the radiosensitivity of human triple-negative breast cancer by inhibiting autophagy. Acta Pharmacol Sin 38:513-523, 2017 Crossref, MedlineGoogle Scholar
69. Cowell IG, Durkacz BW, Tilby MJ: Sensitization of breast carcinoma cells to ionizing radiation by small molecule inhibitors of DNA-dependent protein kinase and ataxia telangiectsia mutated. Biochem Pharmacol 71:13-20, 2005 Crossref, MedlineGoogle Scholar
70. Gasparini P, Lovat F, Fassan M, et al: Protective role of miR-155 in breast cancer through RAD51 targeting impairs homologous recombination after irradiation. Proc Natl Acad Sci U S A 111:4536-4541, 2014 Crossref, MedlineGoogle Scholar
71. Ciszewski WM, Tavecchio M, Dastych J, et al: DNA-PK inhibition by NU7441 sensitizes breast cancer cells to ionizing radiation and doxorubicin. Breast Cancer Res Treat 143:47-55, 2014 Crossref, MedlineGoogle Scholar
72. Fok JHL, Ramos-Montoya A, Vazquez-Chantada M, et al: AZD7648 is a potent and selective DNA-PK inhibitor that enhances radiation, chemotherapy and olaparib activity. Nat Commun 10:5065, 2019 Crossref, MedlineGoogle Scholar
73. Jang NY, Kim DH, Cho BJ, et al: Radiosensitization with combined use of olaparib and PI-103 in triple-negative breast cancer. BMC Cancer 15:89, 2015 Crossref, MedlineGoogle Scholar
74. Tu X, Kahila MM, Zhou Q, et al: ATR inhibition is a promising radiosensitizing strategy for triple-negative breast cancer. Mol Cancer Ther 17:2462-2472, 2018 Crossref, MedlineGoogle Scholar
75. Zenke FT, Zimmermann A, Sirrenberg C, et al: Pharmacological inhibitor of DNA-PK, M3814, potentiates radiotherapy and regresses human tumors in mouse models. Mol Cancer Ther 19:1091-1101, 2020 Crossref, MedlineGoogle Scholar
76. Schmid P, Cortes J, Pusztai L, et al: Pembrolizumab for early triple-negative breast cancer. N Engl J Med 382:810-821, 2020 Crossref, MedlineGoogle Scholar
77. Vanpouille-Box C, Alard A, Aryankalayil MJ, et al: DNA exonuclease Trex1 regulates radiotherapy-induced tumour immunogenicity. Nat Commun 8:15618, 2017 Crossref, MedlineGoogle Scholar
78. Deng L, Liang H, Burnette B, et al: Irradiation and anti-PD-L1 treatment synergistically promote antitumor immunity in mice. J Clin Invest 124:687-695, 2014 Crossref, MedlineGoogle Scholar
79. Verbrugge I, Hagekyriakou J, Sharp LL, et al: Radiotherapy increases the permissiveness of established mammary tumors to rejection by immunomodulatory antibodies. Cancer Res 72:3163-3174, 2012 Crossref, MedlineGoogle Scholar
80. Dovedi SJ, Adlard AL, Lipowska-Bhalla G, et al: Acquired resistance to fractionated radiotherapy can be overcome by concurrent PD-L1 blockade. Cancer Res 74:5458-5468, 2014 Crossref, MedlineGoogle Scholar
81. Vanpouille-Box C, Diamond JM, Pilones KA, et al: TGFbeta is a master regulator of radiation therapy-induced antitumor immunity. Cancer Res 75:2232-2242, 2015 Crossref, MedlineGoogle Scholar
82. Bouquet F, Pal A, Pilones KA, et al: TGFβ1 inhibition increases the radiosensitivity of breast cancer cells in vitro and promotes tumor control by radiation in vivo. Clin Cancer Res 17:6754-6765, 2011 Crossref, MedlineGoogle Scholar
83. Demaria S, Ng B, Devitt ML, et al: Ionizing radiation inhibition of distant untreated tumors (abscopal effect) is immune mediated. Int J Radiat Oncol Biol Phys 58:862-870, 2004 Crossref, MedlineGoogle Scholar
84. Dewan MZ, Galloway AE, Kawashima N, et al: Fractionated but not single-dose radiotherapy induces an immune-mediated abscopal effect when combined with anti-CTLA-4 antibody. Clin Cancer Res 15, 5379-5388, 2009 Crossref, MedlineGoogle Scholar
85. Aguilera TA, Rafat M, Castellini L, et al: Reprogramming the immunological microenvironment through radiation and targeting Axl. Nat Commun 7:13898, 2016 Crossref, MedlineGoogle Scholar
86. Marvaso G, Barone A, Amodio N, et al: Sphingosine analog fingolimod (FTY720) increases radiation sensitivity of human breast cancer cells in vitro. Cancer Biol Ther 15:797-805, 2014 Crossref, MedlineGoogle Scholar
87. Tsoutsou PG, Zaman K, Martin Lluesma S, et al: Emerging opportunities of radiotherapy combined with immunotherapy in the era of breast cancer heterogeneity. Front Oncol 8:609, 2018 Crossref, MedlineGoogle Scholar
88. Ye JC, Formenti SC: Integration of radiation and immunotherapy in breast cancer—treatment implications. Breast 38:66-74, 2018 Crossref, MedlineGoogle Scholar
89. Yao Z, Peng P, Xu D, et al: EGFR inhibitor C225 increases the radio-sensitivity of human breast cancer cells. Asian Pac J Cancer Prev 20:311-319, 2019 Crossref, MedlineGoogle Scholar
90. El Guerrab A, Bamdad M, Bignon, YJ, et al: Anti-EGFR monoclonal antibodies enhance sensitivity to DNA-damaging agents in BRCA1-mutated and PTEN-wild-type triple-negative breast cancer cells. Mol Carcinog 56:1383-1394, 2017 Crossref, MedlineGoogle Scholar
91. Qu YY, Hu SL, Xu XY, et al: Nimotuzumab enhances the radiosensitivity of cancer cells in vitro by inhibiting radiation-induced DNA damage repair. PLoS One 8:e70727, 2013 Crossref, MedlineGoogle Scholar
92. Rao GS, Murray S, Ethier SP: Radiosensitization of human breast cancer cells by a novel ErbB family receptor tyrosine kinase inhibitor. Int J Radiat Oncol Biol Phys 48:1519-1528, 2000 Crossref, MedlineGoogle Scholar
93. He G, Di X, Yan J, et al: Silencing human epidermal growth factor receptor-3 radiosensitizes human luminal a breast cancer cells. Cancer Sci 109:3774-3782, 2018 Crossref, MedlineGoogle Scholar
94. Contessa JN, Abell A, Mikkelsen RB, et al: Compensatory ErbB3/c-Src signaling enhances carcinoma cell survival to ionizing radiation. Breast Cancer Res Treat 95:17-27, 2006 Crossref, MedlineGoogle Scholar
95. Lammering G, Lin PS, Contessa JN, et al: Adenovirus-mediated overexpression of dominant negative epidermal growth factor receptor-CD533 as a gene therapeutic approach radiosensitizes human carcinoma and malignant glioma cells. Int J Radiat Oncol Biol Phys 51:775-784, 2001 Crossref, MedlineGoogle Scholar
96. Contessa JN, Reardon DB, Todd D, et al: The inducible expression of dominant-negative epidermal growth factor receptor-CD533 results in radiosensitization of human mammary carcinoma cells. Clin Cancer Res 5:405-411, 1999 MedlineGoogle Scholar
97. Ghorab MM, Alsaid MS, Soliman AM: Dual EGFR/HER2 inhibitors and apoptosis inducers: New benzo[g]quinazoline derivatives bearing benzenesulfonamide as anticancer and radiosensitizers. Bioorg Chem 80:611-620, 2018 Crossref, MedlineGoogle Scholar
98. Fukutome M, Maebayashi K, Nasu S, et al: Enhancement of radiosensitivity by dual inhibition of the HER family with ZD1839 (“Iressa”) and trastuzumab (“Herceptin”). Int J Radiat Oncol Biol Phys 66:528-536, 2006 Crossref, MedlineGoogle Scholar
99. Heravi M, Kumala S, Rachid Z, et al: ZRBA1, a mixed EGFR/DNA targeting molecule, potentiates radiation response through delayed DNA damage repair process in a triple negative breast cancer model. Int J Radiat Oncol Biol Phys 92:399-406, 2015 Crossref, MedlineGoogle Scholar
100. Li P, Veldwijk MR, Zhang Q, et al: Co-inhibition of epidermal growth factor receptor and insulin-like growth factor receptor 1 enhances radiosensitivity in human breast cancer cells. BMC Cancer 13:297, 2013 Crossref, MedlineGoogle Scholar
101. Wen B, Deutsch E, Marangoni E, et al: Tyrphostin AG 1024 modulates radiosensitivity in human breast cancer cells. Br J Cancer 85:2017-2021, 2001 Crossref, MedlineGoogle Scholar
102. Tuner BC, Haffty BG, Narayanan L, et al: Insulin-like growth factor-I receptor overexpression mediates cellular radioresistance and local breast cancer recurrence after lumpectomy and radiation. Cancer Res 57:3079-3083, 1997 MedlineGoogle Scholar
103. Koo T, Cho BJ, Kim DH, et al: MicroRNA-200c increases radiosensitivity of human cancer cells with activated EGFR-associated signaling. Oncotarget 8:65457-65468, 2017 Crossref, MedlineGoogle Scholar
104. Lee KM, Choi EJ, Kim IA: microRNA-7 increases radiosensitivity of human cancer cells with activated EGFR-associated signaling. Radiother Oncol 101:171-176, 2011 Crossref, MedlineGoogle Scholar
105. Cao N, Li S, Wang Z et al: NF-kappaB-mediated HER2 overexpression in radiation-adaptive resistance. Radiat Res 171:9-21, 2009 Crossref, MedlineGoogle Scholar
106. Lai Y, Yu X, Lin X, et al: Inhibition of mTOR sensitizes breast cancer stem cells to radiation-induced repression of self-renewal through the regulation of MnSOD and Akt. Int J Mol Med 37:369-377, 2016 Crossref, MedlineGoogle Scholar
107. Kuger S, Cörek E, Polat B, et al: Novel PI3K and mTOR inhibitor NVP-BEZ235 radiosensitizes breast cancer cell lines under normoxic and hypoxic conditions. Breast Cancer (Auckl) 8:39-49, 2014 MedlineGoogle Scholar
108. Sizemore GM, Balakrishnan S, Thies KA, et al: Stromal PTEN determines mammary epithelial response to radiotherapy. Nat Commun 9:2783, 2018 Crossref, MedlineGoogle Scholar
109. Weng LP, Smith WM, Dahia PL, et al: PTEN suppresses breast cancer cell growth by phosphatase activity-dependent G1 arrest followed by cell death. Cancer Res. 59:5808-5814, 1999 MedlineGoogle Scholar
110. Toulany M, Schickfluss TA, Eicheler W, et al: Impact of oncogenic K-RAS on YB-1 phosphorylation induced by ionizing radiation. Breast Cancer Res 13:R28, 2011 Crossref, MedlineGoogle Scholar
111. Yan Y, Greer PM, Cao PT, et al: RAC1 GTPase plays an important role in gamma-irradiation induced G2/M checkpoint activation. Breast Cancer Res 14:R60, 2012 Crossref, MedlineGoogle Scholar
112. Albert JM, Kim KW, Cao C, et al: Targeting the Akt/mammalian target of rapamycin pathway for radiosensitization of breast cancer. Mol Cancer Ther 5:1183-1189, 2006 Crossref, MedlineGoogle Scholar
113. Paglin S, Lee NY, Nakar C, et al: Rapamycin-sensitive pathway regulates mitochondrial membrane potential, autophagy, and survival in irradiated MCF-7 cells. Cancer Res 65:11061-11070, 2005 Crossref, MedlineGoogle Scholar
114. Fatehi D, Soltani A, Ghatrehsamani M: SRT1720, a potential sensitizer for radiotherapy and cytotoxicity effects of NVB-BEZ235 in metastatic breast cancer cells. Pathol Res Pract 214:889-895, 2018 Crossref, MedlineGoogle Scholar
115. Masoumi H, Soltani A, Ghatrehsamani M: The beneficial role of SIRT1 activator on chemo- and radiosensitization of breast cancer cells in response to IL-6. Mol Biol Rep 47:129-139, 2020 Crossref, MedlineGoogle Scholar
116. Zhang X, Li Y, Wang D, et al: miR-22 suppresses tumorigenesis and improves radiosensitivity of breast cancer cells by targeting Sirt1. Biol Res 50:27, 2017 Crossref, MedlineGoogle Scholar
117. Maggiorella L, Deutsch E, Frascogna V, et al: Enhancement of radiation response by roscovitine in human breast carcinoma in vitro and in vivo. Cancer Res 63:2513-2517, 2003 MedlineGoogle Scholar
118. Liu X, Sun C, Jin X, et al: Genistein enhances the radiosensitivity of breast cancer cells via G(2)/M cell cycle arrest and apoptosis. Molecules 18:13200-13217, 2013 Crossref, MedlineGoogle Scholar
119. Quereda V, Bayle S, Vena F, et al: Therapeutic targeting of CDK12/CDK13 in triple-negative breast cancer. Cancer Cell 36:545-558.e547, 2019 Crossref, MedlineGoogle Scholar
120. Pesch A, Hirsh NH, Chandler BC, et al: Short term CDK4/6 inhibition radiosensitizes estrogen receptor positive breast cancers. Clin Cancer Res 26:6568-6580, 2020 Crossref, MedlineGoogle Scholar
121. Robinson TJ, Liu JC, Vizeacoumar F, et al: RB1 status in triple negative breast cancer cells dictates response to radiation treatment and selective therapeutic drugs. PLoS One 8:e78641, 2013 Crossref, MedlineGoogle Scholar
122. Fernandez-Aroca DM, Roche O, Sabater S, et al: P53 pathway is a major determinant in the radiosensitizing effect of Palbociclib: Implication in cancer therapy. Cancer Lett 451:23-33, 2019 Crossref, MedlineGoogle Scholar
123. Bao-Lei T, Zhu-Zhong M, Yi S, et al: Knocking down PML impairs p53 signaling transduction pathway and suppresses irradiation induced apoptosis in breast carcinoma cell MCF-7. J Cell Biochem 97:561-571, 2006 Crossref, MedlineGoogle Scholar
124. Wang H, Oliver P, Zhang Z, et al: Chemosensitization and radiosensitization of human cancer by antisense anti-MDM2 oligonucleotides: In vitro and in vivo activities and mechanisms. Ann N Y Acad Sci 1002:217-235, 2003 Crossref, MedlineGoogle Scholar
125. Zhang Z, Wang H, Prasad G, et al: Radiosensitization by antisense anti-MDM2 mixed-backbone oligonucleotide in in vitro and in vivo human cancer models. Clin Cancer Res 10:1263-1273, 2004 Crossref, MedlineGoogle Scholar
126. Hu X, Xing L, Jiao Y, et al: BTG2 overexpression increases the radiosensitivity of breast cancer cells in vitro and in vivo. Oncol Res 20:457-465, 2013 Crossref, MedlineGoogle Scholar
127. Zhu R, Li W, Xu Y, et al: Upregulation of BTG1 enhances the radiation sensitivity of human breast cancer in vitro and in vivo. Oncol Rep 34:3017-3024, 2015 Crossref, MedlineGoogle Scholar
128. Speers C, Zhao SG, Kothari V, et al: Maternal embryonic leucine zipper kinase (MELK) as a novel mediator and biomarker of radioresistance in human breast cancer. Clin Cancer Res 22:5864-5875, 2016 Crossref, MedlineGoogle Scholar
129. Bridges KA, Hirai H, Buser CA, et al: MK-1775, a novel Wee1 kinase inhibitor, radiosensitizes p53-defective human tumor cells. Clin Cancer Res 17:5638-5648, 2011 Crossref, MedlineGoogle Scholar
130. Li C, Du L, Ren Y, et al: SKP2 promotes breast cancer tumorigenesis and radiation tolerance through PDCD4 ubiquitination. J Exp Clin Cancer Res 38:76, 2019 Crossref, MedlineGoogle Scholar
131. Ren YQ, Fu F, Han J: MiR-27a modulates radiosensitivity of triple-negative breast cancer (TNBC) cells by targeting CDC27. Med Sci Monit 21:1297-1303, 2015 Crossref, MedlineGoogle Scholar
132. Chandler BC, Moubadder L, Ritter CL, et al: TTK inhibition radiosensitizes basal-like breast cancer through impaired homologous recombination. J Clin Invest 130:958-973, 2020 Crossref, MedlineGoogle Scholar
133. Yan Y, Cao PT, Greer PM, et al: Protein phosphatase 2A has an essential role in the activation of gamma-irradiation-induced G2/M checkpoint response. Oncogene 29:4317-4329, 2010 Crossref, MedlineGoogle Scholar
134. Benada J, Burdova K, Lidak T, et al: Polo-like kinase 1 inhibits DNA damage response during mitosis. Cell Cycle 14:219-231, 2015 Crossref, MedlineGoogle Scholar
135. Brassesco MS, Pezuk JA, Salomão KB, et al: PLK1 inhibition radiosensitizes breast cancer cells, but shows low efficacy as monotherapy or in combination with other cytotoxic drugs. Anticancer Agents Med Chem 18:1252-1257, 2018 Crossref, MedlineGoogle Scholar
136. Yin L, Gao Y, Zhang X, et al: Niclosamide sensitizes triple-negative breast cancer cells to ionizing radiation in association with the inhibition of Wnt/beta-catenin signaling. Oncotarget 7:42126-42138, 2016 Crossref, MedlineGoogle Scholar
137. Li JY, Li YY, Jin W, et al: ABT-737 reverses the acquired radioresistance of breast cancer cells by targeting Bcl-2 and Bcl-xL. J Exp Clin Cancer Res 31:102, 2012 Crossref, MedlineGoogle Scholar
138. Zhou KX, Xie LH, Peng X, et al: CXCR4 antagonist AMD3100 enhances the response of MDA-MB-231 triple-negative breast cancer cells to ionizing radiation. Cancer Lett 418:196-203, 2018 Crossref, MedlineGoogle Scholar
139. Lin F, Luo J, Gao W, et al: COX-2 promotes breast cancer cell radioresistance via p38/MAPK-mediated cellular anti-apoptosis and invasiveness. Tumour Biol 34:2817-2826, 2013 Crossref, MedlineGoogle Scholar
140. Oladghaffari M, Shabestani Monfared A, Farajollahi A, et al: MLN4924 and 2DG combined treatment enhances the efficiency of radiotherapy in breast cancer cells. Int J Radiat Biol 93:590-599, 2017 Crossref, MedlineGoogle Scholar
141. Yang D, Tan M, Wang G, et al: The p21-dependent radiosensitization of human breast cancer cells by MLN4924, an investigational inhibitor of NEDD8 activating enzyme. PloS one 7:e34079, 2012 Crossref, MedlineGoogle Scholar
142. Yang D, Zhao Y, Li AY, et al: Smac-mimetic compound SM-164 induces radiosensitization in breast cancer cells through activation of caspases and induction of apoptosis. Breast Cancer Res Treat 133:189-199, 2011 Crossref, MedlineGoogle Scholar
143. Hu X, Ding D, Zhang J, et al: Knockdown of lncRNA HOTAIR sensitizes breast cancer cells to ionizing radiation through activating miR-218. Biosci Rep 39:BSR20181038, 2019 Crossref, MedlineGoogle Scholar
144. Sakakura C, Sweeney EA, Shirahama T, et al: Overexpression of bax sensitizes human breast cancer MCF-7 cells to radiation-induced apoptosis. Int J Cancer 67:101-105, 1996 Crossref, MedlineGoogle Scholar
145. Lu L, Dong J, Wang L, et al: Activation of STAT3 and Bcl-2 and reduction of reactive oxygen species (ROS) promote radioresistance in breast cancer and overcome of radioresistance with niclosamide. Oncogene 37:5292-5304, 2018 Crossref, MedlineGoogle Scholar
146. Zou M, Li Y, Xia S, et al: Knockdown of CAVEOLIN-1 sensitizes human basal-like triple-negative breast cancer cells to radiation. Cell Physiol Biochem 44:778-791, 2017 Crossref, MedlineGoogle Scholar
147. Zhang L, Bochkur Dratver M, Yazal T, et al: Mebendazole potentiates radiation therapy in triple-negative breast cancer. Int J Radiat Oncol Biol Phys 103:195-207, 2019 Crossref, MedlineGoogle Scholar
148. Johnson J, Chow Z, Napier D, et al: Targeting PI3K and AMPKα signaling alone or in combination to enhance radiosensitivity of triple negative breast cancer. Cells 9:1253, 2020 CrossrefGoogle Scholar
149. Chaachouay H, Ohneseit P, Toulany M, et al: Autophagy contributes to resistance of tumor cells to ionizing radiation. Radiother Oncol 99:287-292, 2011 Crossref, MedlineGoogle Scholar
150. Chin C, Bae JH, Kim MJ, et al: Radiosensitization by targeting radioresistance-related genes with protein kinase A inhibitor in radioresistant cancer cells. Exp Mol Med 37:608-618, 2005 Crossref, MedlineGoogle Scholar
151. Apel A, Herr I, Schwarz H, et al: Blocked autophagy sensitizes resistant carcinoma cells to radiation therapy. Cancer Res 68:1485-1495, 2008 Crossref, MedlineGoogle Scholar
152. Kim KW, Moretti L, Mitchel LR, et al: Endoplasmic reticulum stress mediates radiation-induced autophagy by perk-eIF2alpha in caspase-3/7-deficient cells. Oncogene 29:3241-3251, 2010 Crossref, MedlineGoogle Scholar
153. Lei F, Zheng X, Liu Y, et al: Different roles of CHOP and JNK in mediating radiation-induced autophagy and apoptosis in breast cancer cells. Radiat Res 185:539-548, 2016 Crossref, MedlineGoogle Scholar
154. Han MW, Lee JC, Choi JY, et al: Autophagy inhibition can overcome radioresistance in breast cancer cells through suppression of TAK1 activation. Anticancer Res 34:1449-1455, 2014 MedlineGoogle Scholar
155. Sanli T, Rashid A, Liu C, et al: Ionizing radiation activates AMP-activated kinase (AMPK): A target for radiosensitization of human cancer cells. Int J Radiat Oncol Biol Phys 78:221-229, 2010 Crossref, MedlineGoogle Scholar
156. Song CW, Lee H, Dings RP, et al: Metformin kills and radiosensitizes cancer cells and preferentially kills cancer stem cells. Sci Rep 2:362, 2012 Crossref, MedlineGoogle Scholar
157. Zhang L, Bailleul J, Yazal T, et al: PK-M2-mediated metabolic changes in breast cancer cells induced by ionizing radiation. Breast Cancer Res Treat 178:75-86, 2019 Crossref, MedlineGoogle Scholar
158. Zha F, Min J, Zho Y, et al: Inhibition of Glut1 by WZB117 sensitizes radioresistant breast cancer cells to irradiation. Cancer Chemother Pharmacol 77:963-972, 2016 Crossref, MedlineGoogle Scholar
159. He WS, Dai XF, Jin M, et al: Hypoxia-induced autophagy confers resistance of breast cancer cells to ionizing radiation. Oncol Res 20:251-258, 2012 Crossref, MedlineGoogle Scholar
160. Jia Y, Weng Z, Wang C, et al: Increased chemosensitivity and radiosensitivity of human breast cancer cell lines treated with novel functionalized single-walled carbon nanotubes. Oncol Lett 13:206-214, 2017 Crossref, MedlineGoogle Scholar
161. Zhong R, Xu H, Chen G, et al: The role of hypoxia-inducible factor-1alpha in radiation-induced autophagic cell death in breast cancer cells. Tumour Biol 36:7077-7083, 2015 Crossref, MedlineGoogle Scholar
162. Mehta M, Basalingappa K, Griffith JN, et al: HuR silencing elicits oxidative stress and DNA damage and sensitizes human triple-negative breast cancer cells to radiotherapy. Oncotarget 7:64820-64835, 2016 Crossref, MedlineGoogle Scholar
163. Martinel Lamas DJ, CortinaJE, Ventura C, et al: Enhancement of ionizing radiation response by histamine in vitro and in vivo in human breast cancer. Cancer Biol Ther 16:137-148, 2015 Crossref, MedlineGoogle Scholar
164. Rodman SN, Spence JM, Ronnfeldt TJ, et al: Enhancement of radiation response in breast cancer stem cells by inhibition of thioredoxin- and glutathione-dependent metabolism. Radiat Res 186:385-395, 2016 Crossref, MedlineGoogle Scholar
165. Atkinson RL, ZhangM, Diagaradjane P, et al: Thermal enhancement with optically activated gold nanoshells sensitizes breast cancer stem cells to radiation therapy. Sci Transl Med 2:55ra79, 2010 Crossref, MedlineGoogle Scholar
166. Lettau K, Zips D, Toulany M: Simultaneous targeting of RSK and AKT efficiently inhibits YB-1-mediated repair of ionizing radiation-induced DNA double strand breaks in breast cancer cells. Int J Radiat Oncol Biol Phys doi: https://doi.org/10.1016/j.ijrobp.2020.09.00 [epub ahead of print on September 12, 2020] Google Scholar
167. Mehta M, Griffith J, Panneerselvam J, et al: Regorafenib sensitizes human breast cancer cells to radiation by inhibiting multiple kinases and inducing DNA damage. Int J Radiat Biol 2:1-12, 2020 CrossrefGoogle Scholar
168. Lee YC, Wang WL, Chang WC, et al: Tribbles homolog 3 involved in radiation response of triple negative breast cancer cells by regulating Notch1 activation. Cancers (Basel) 11:127, 2019 CrossrefGoogle Scholar
169. Peng JH, Wang XL, Ran L, et al: Inhibition of Notch signaling pathway enhanced the radiosensitivity of breast cancer cells. J Cell Biochem 119:8398-8409, 2018 Crossref, MedlineGoogle Scholar
170. Farhood B, Goradel NH, Mortezaee K, et al: Melatonin as an adjuvant in radiotherapy for radioprotection and radiosensitization. Clin Transl Oncol 21:268-279, 2019 Crossref, MedlineGoogle Scholar
171. Taghizadeh B, Ghavami L, Nikoofar A, et al: Equol as a potent radiosensitizer in estrogen receptor-positive and -negative human breast cancer cell lines. Breast Cancer 22:382-390, 2015 Crossref, MedlineGoogle Scholar
172. Bigdeli B, Goliaei B, Masoudi-Khoram N, et al: Enterolactone: A novel radiosensitizer for human breast cancer cell lines through impaired DNA repair and increased apoptosis. Toxicol Appl Pharmacol 313:180-194, 2016 Crossref, MedlineGoogle Scholar
173. Ding X, YangQ, Kong X, et al: Radiosensitization effect of Huaier on breast cancer cells. Oncol Rep 35:2843-2850, 2016 Crossref, MedlineGoogle Scholar
174. Su YJ, Huang SY, Ni YH, et al: Anti-tumor and radiosensitization effects of N-butylidenephthalide on human breast cancer cells. Molecules 23:240, 2018 CrossrefGoogle Scholar
175. Wang J, Liu Q, Yang Q: Radiosensitization effects of berberine on human breast cancer cells. Int J Mol Med 30:1166-1172, 2012 Crossref, MedlineGoogle Scholar
176. Kim MY, Park SJ, Shim JW, et al: Naphthazarin enhances ionizing radiation-induced cell cycle arrest and apoptosis in human breast cancer cells. Int J Oncol 46:1659-1666, 2015 Crossref, MedlineGoogle Scholar
177. Famoso JM, Laughlin B, McBride A, et al: Pentoxifylline and vitamin E drug compliance after adjuvant breast radiation therapy. Adv Radiat Oncol 3:19-24, 2018 Crossref, MedlineGoogle Scholar
178. Kaidar-Person O, Marks LB, Jones EL: Pentoxifylline and vitamin E for treatment or prevention of radiation-induced fibrosis in patients with breast cancer. Breast J 24:816-819, 2018 Crossref, MedlineGoogle Scholar
179. Magnusson M, Höglund P, Johansson K, et al: Pentoxifylline and vitamin E treatment for prevention of radiation-induced side-effects in women with breast cancer: A phase two, double-blind, placebo-controlled randomised clinical trial (Ptx-5). Eur J Cancer 45:2488-2495, 2009 Crossref, MedlineGoogle Scholar
180. Choi YJ, Heo K, Park HS, et al: The resveratrol analog HS-1793 enhances radiosensitivity of mouse-derived breast cancer cells under hypoxic conditions. Int J Oncol 49:1479-1488, 2016 Crossref, MedlineGoogle Scholar
181. Lacerda L, Reddy JP, Liu D, et al: Simvastatin radiosensitizes differentiated and stem-like breast cancer cell lines and is associated with improved local control in inflammatory breast cancer patients treated with postmastectomy radiation. Stem Cells Transl Med 3:849-856, 2014 Crossref, MedlineGoogle Scholar
Downloaded 953 times

COMPANION ARTICLES

No companion articles

ARTICLE CITATION

DOI: 10.1200/PO.20.00297 JCO Precision Oncology no. 5 (2021) 245-264. Published online January 25, 2021.

ASCO Career Center