Radiosensitivity Is an Acquired Vulnerability of PARPi-Resistant BRCA1-Deficient Tumors.
- Barazas M Division of Molecular Pathology, Oncode Institute, the Netherlands Cancer Institute, Amsterdam, the Netherlands.
- Gasparini A Division of Radiation Oncology, the Netherlands Cancer Institute, Amsterdam, the Netherlands.
- Huang Y Division of Molecular Pathology, Oncode Institute, the Netherlands Cancer Institute, Amsterdam, the Netherlands.
- Küçükosmanoğlu A Division of Molecular Pathology, Oncode Institute, the Netherlands Cancer Institute, Amsterdam, the Netherlands.
- Annunziato S Division of Molecular Pathology, Oncode Institute, the Netherlands Cancer Institute, Amsterdam, the Netherlands.
- Bouwman P Division of Molecular Pathology, Oncode Institute, the Netherlands Cancer Institute, Amsterdam, the Netherlands.
- Sol W Division of Molecular Pathology, Oncode Institute, the Netherlands Cancer Institute, Amsterdam, the Netherlands.
- Kersbergen A Division of Molecular Pathology, Oncode Institute, the Netherlands Cancer Institute, Amsterdam, the Netherlands.
- Proost N Mouse Clinic for Cancer and Aging Research (MCCA), Preclinical Intervention Unit, the Netherlands Cancer Institute, Amsterdam, the Netherlands.
- de Korte-Grimmerink R Mouse Clinic for Cancer and Aging Research (MCCA), Preclinical Intervention Unit, the Netherlands Cancer Institute, Amsterdam, the Netherlands.
- van de Ven M Mouse Clinic for Cancer and Aging Research (MCCA), Preclinical Intervention Unit, the Netherlands Cancer Institute, Amsterdam, the Netherlands.
- Jonkers J Division of Molecular Pathology, Oncode Institute, the Netherlands Cancer Institute, Amsterdam, the Netherlands. sven.rottenberg@vetsuisse.unibe.ch j.jonkers@nki.nl g.borst@nki.nl.
- Borst GR Division of Radiation Oncology, the Netherlands Cancer Institute, Amsterdam, the Netherlands. sven.rottenberg@vetsuisse.unibe.ch j.jonkers@nki.nl g.borst@nki.nl.
- Rottenberg S Division of Molecular Pathology, Oncode Institute, the Netherlands Cancer Institute, Amsterdam, the Netherlands. sven.rottenberg@vetsuisse.unibe.ch j.jonkers@nki.nl g.borst@nki.nl.
- 2018-12-12
Published in:
- Cancer research. - 2019
Animals
BRCA1 Protein
Cell Cycle Proteins
DNA Repair
DNA-Binding Proteins
Disease Models, Animal
Drug Resistance, Neoplasm
Gene Expression Regulation, Neoplastic
Homologous Recombination
Humans
Mad2 Proteins
Mice
Neoplasms
Poly(ADP-ribose) Polymerase Inhibitors
Poly(ADP-ribose) Polymerases
Radiation Tolerance
Telomere-Binding Proteins
Tumor Suppressor Proteins
Tumor Suppressor p53-Binding Protein 1
English
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.
- Language
-
- English
- Open access status
- bronze
- Identifiers
-
- DOI 10.1158/0008-5472.CAN-18-2077
- PMID 30530501
- Persistent URL
- https://sonar.ch/global/documents/203365
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