Journal
CANCER RESEARCH
Volume 79, Issue 3, Pages 452-460Publisher
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/0008-5472.CAN-18-2077
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Funding
- Dutch Cancer Society [KWF 2011-5220, 2014-6532]
- Netherlands Organization for Scientific Research [VICI 91814643, NGI 93512009]
- Netherlands Organization for Scientific Research (Cancer Genomics Netherlands)
- Netherlands Organization for Scientific Research (National Roadmap Grant for Large-Scale Research Facilities)
- Swiss National Science Foundation [310030_179360]
- Swiss Cancer League [KLS-4282-08-2017]
- Swiss Cancer League (ERC) [CoG-681572]
- Swiss Cancer League (ERC Synergy Grant) [319661]
- Swiss National Science Foundation (SNF) [310030_179360] Funding Source: Swiss National Science Foundation (SNF)
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The defect in homologous recombination (HR) found in BRCA1-associated cancers can be therapeutically exploited by treatment with DNA-damaging agents and PARP inhibitors. We and others previously reported that BRCA1-deficient tumors are initially hypersensitive to the inhibition of topoisomerase I/II and PARP, but acquire drug resistance through restoration of HR activity by the loss of end-resection antagonists of the 53BP1/RIF1/REV7/Shieldin/CST pathway. Here, we identify radiotherapy as an acquired vulnerability of 53BP1; BRCA1-deficient cells in vitro and in vivo. In contrast to the radioresistance caused by HR restoration through BRCA1 reconstitution, HR restoration by 53BP1 pathway inactivation further increases radiosensitivity. This highlights the relevance of this pathway for the repair of radiotherapy-induced damage. Moreover, our data show that BRCA1-mutated tumors that acquire drug resistance due to BRCA1-independent HR restoration can be targeted by radiotherapy. Significance: These findings uncover radiosensitivity as a novel, therapeutically viable vulnerability of BRCA1-deficient mouse mammary cells that have acquired drug resistance due to the loss of the 53BP1 pathway.
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