Figure S5 from Radiosensitivity Is an Acquired Vulnerability of PARPi-Resistant BRCA1-Deficient Tumors

Barazas, Marco; Gasparini, Alessia; Huang, Yike; Küçükosmanoğlu, Asli; Annunziato, Stefano; Bouwman, Peter; Sol, Wendy; Kersbergen, Ariena; Proost, Natalie; de Korte-Grimmerink, Renske; van de Ven, Marieke; Jonkers, Jos; Borst, Gerben R.; Rottenberg, Sven

doi:10.1158/0008-5472.22422858.v1

00085472can182077-sup-204827_2_supp_5165303_pq8c8z.pdf (477.48 kB)

Figure S5 from Radiosensitivity Is an Acquired Vulnerability of PARPi-Resistant BRCA1-Deficient Tumors

journal contribution

posted on 2023-03-31, 03:00 authored by Marco Barazas, Alessia Gasparini, Yike Huang, Asli Küçükosmanoğlu, 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

Supplementary Figure S5. Radiosensitization of BRCA1 deficient cells by 53BP1 depletion is dependent on DNA-PK. Related to Figure 2.

Funding

Dutch Cancer Society

Netherlands Organization for Scientific Research

Swiss National Science Foundation

Swiss Cancer League

History

ARTICLE 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 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. 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.