Radiosensitivity Is an Acquired Vulnerability of PARPi-Resistant BRCA1-Deficient Tumors

Overview

Journal Cancer Res

Specialty Oncology

Date 2018 Dec 12

PMID 30530501

Citations 31

Authors

Marco Barazas

Alessia Gasparini

Yike Huang

Asli Kucukosmanoglu

Stefano Annunziato

Peter Bouwman

Wendy Sol

Ariena Kersbergen

Natalie Proost

Renske de Korte-Grimmerink

Marieke van de Ven

Jos Jonkers

Gerben R Borst

Sven Rottenberg

Affiliations

Soon will be listed here.

Abstract

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 and . 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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