Radiosensitivity Is an Acquired Vulnerability of PARPi-Resistant BRCA1-Deficient Tumors.
Marco BarazasAlessia GaspariniYike HuangAsli KüçükosmanoğluStefano AnnunziatoPeter BouwmanWendy SolAriena KersbergenNatalie ProostRenske de Korte-GrimmerinkMarieke van de VenJos JonkersGerben R BorstSven RottenbergPublished in: Cancer research (2018)
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.
Keyphrases
- breast cancer risk
- dna damage
- dna repair
- early stage
- induced apoptosis
- climate change
- radiation therapy
- magnetic resonance
- radiation induced
- locally advanced
- squamous cell carcinoma
- cell cycle arrest
- oxidative stress
- magnetic resonance imaging
- wild type
- cell death
- mycobacterium tuberculosis
- signaling pathway
- cell proliferation
- electronic health record
- machine learning
- pulmonary tuberculosis
- artificial intelligence
- contrast enhanced
- high glucose