Abstract
Standard radiation therapy (RT) does not reliably provide locoregional control for women with multinode-positive breast cancer and triple-negative breast cancer (TNBC). We hypothesized that CDK4/6 inhibition (CDK4/6i) would increase the radiosensitivity not only of estrogen receptor–positive (ER+) cells, but also of TNBC that expresses retinoblastoma (RB) protein. We found that CDK4/6i radiosensitized RB WT TNBC (n = 4, radiation enhancement ratio [rER]: 1.49–2.22) but failed to radiosensitize RB-null TNBC (n = 3, rER: 0.84–1.00). RB expression predicted response to CDK4/6i + RT (R2 = 0.84), and radiosensitization was lost in ER+/TNBC cells (rER: 0.88–1.13) after RB1 knockdown in isogenic and nonisogenic models. CDK4/6i suppressed homologous recombination (HR) in RB WT cells but not in RB-null cells or isogenic models of RB1 loss; HR competency was rescued with RB reexpression. Radiosensitization was independent of nonhomologous end joining and the known effects of CDK4/6i on cell cycle arrest. Mechanistically, RB and RAD51 interact in vitro to promote HR repair. CDK4/6i produced RB-dependent radiosensitization in TNBC xenografts but not in isogenic RB1-null xenografts. Our data provide the preclinical rationale for a clinical trial expanding the use of CDK4/6i + RT to difficult-to-control RB-intact breast cancers (including TNBC) and nominate RB status as a predictive biomarker of therapeutic efficacy.
Highlights
Breast cancer is a heterogeneous group of diseases where treatment options – and often treatment outcomes – are tied to the presence or absence of molecular markers including the estrogen receptor (ER), progesterone receptor (PR), and the human epidermal growth factor receptor 2 (HER2)
We demonstrate that CDK4/6 inhibition and radiotherapy led to an RB
Cells treated with a CDK4/6 inhibitor in the presence of RB were radiosensitized through cell cycleindependent impairment of homologous recombination (HR) activity and not NHEJ (Figure 3); neither radiation sensitivity nor HR activity was affected in RB null triple negative breast cancers (TNBC) cell lines (Figure 2)
Summary
Breast cancer is a heterogeneous group of diseases where treatment options – and often treatment outcomes – are tied to the presence or absence of molecular markers including the estrogen receptor (ER), progesterone receptor (PR), and the human epidermal growth factor receptor 2 (HER2). These receptors serve as drivers of tumorigenesis and disease progression, and ER+ or HER2-expressing tumors respond to inhibitors targeting either hormone-mediated or HER2-mediated signaling pathways, respectively. Varying results have been reported, but based on improved invasive disease-free survival in the MonarchE trial, abemaciclib was the first CDK4/6 inhibitor to be approved as an adjuvant therapy in women with high-risk, non-metastatic, ER+ breast cancer with a high Ki67 score
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