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 (2019). Radiosensitivity Is an Acquired Vulnerability of PARPi-Resistant BRCA1-Deficient Tumors. Cancer research, 79(3), pp. 452-460. American Association for Cancer Research AACR 10.1158/0008-5472.CAN-18-2077

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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 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.

Item Type:

Journal Article (Original Article)

Division/Institute:

05 Veterinary Medicine > Research Foci > Host-Pathogen Interaction
05 Veterinary Medicine > Department of Infectious Diseases and Pathobiology (DIP) > Institute of Animal Pathology
05 Veterinary Medicine > Department of Infectious Diseases and Pathobiology (DIP)

UniBE Contributor:

Rottenberg, Sven

Subjects:

500 Science > 570 Life sciences; biology
600 Technology > 610 Medicine & health
600 Technology > 630 Agriculture

ISSN:

0008-5472

Publisher:

American Association for Cancer Research AACR

Language:

English

Submitter:

Achim Braun Parham

Date Deposited:

31 May 2019 13:10

Last Modified:

24 Oct 2019 13:58

Publisher DOI:

10.1158/0008-5472.CAN-18-2077

PubMed ID:

30530501

BORIS DOI:

10.7892/boris.127530

URI:

https://boris.unibe.ch/id/eprint/127530

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