Genomics-Driven Tumor Treatments
Modulating the Radiation Response for Improved Outcomes in Breast Cancer
2Department of Pharmacology, University of Michigan, Ann Arbor, MI
3Rogel Cancer Center, University of Michigan, Ann Arbor, MI
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.
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.
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.
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).
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.
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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
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.
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.
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.
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.
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.
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