| Autor: |
Pesch AM; Department of Radiation Oncology.; Department of Pharmacology., Hirsh NH; Department of Radiation Oncology., Michmerhuizen AR; Department of Radiation Oncology.; Program in Cellular and Molecular Biology, and., Jungles KM; Department of Radiation Oncology.; Department of Pharmacology., Wilder-Romans K; Department of Radiation Oncology., Chandler BC; Department of Radiation Oncology., Liu M; Department of Radiation Oncology., Lerner LM; Department of Radiation Oncology., Nino CA; Department of Radiation Oncology.; Program in Cellular and Molecular Biology, and., Ward C; Department of Radiation Oncology., Cobain EF; Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA., Lawrence TS; Department of Radiation Oncology., Pierce LJ; Department of Radiation Oncology., Rae JM; Department of Pharmacology.; Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA., Speers CW; Department of Radiation Oncology. |
| Abstrakt: |
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. |
