Secondary mutation of BRCA1/2 as a mechanism of drug resistance in BRCA1/2-mutated cancer
Toshiyasu Taniguchi
Fred Hutchinson Cancer Research Center, USA
DNA-damaging platinum compounds, cisplatin and carboplatin, are widely used anti-cancer drugs. The breast/ovarian cancer susceptibility genes, BRCA1 and BRCA2, are required for cellular resistance to cisplatin/carboplatin, because they regulate homologous recombination, which is required for repair of DNA lesions caused by platinum treatment. Consistently, ovarian carcinomas with mutations in BRCA1/2 are sensitive to platinum compounds. However, such carcinomas ultimately develop platinum resistance. This acquired resistance is a serious problem in the treatment of ovarian cancer, but its mechanism is largely unknown. Poly(ADP-ribose) polymerase (PARP) inhibitors specifically kill BRCA1/2-deficient tumour cells and are expected to become a therapeutic option for the treatment of BRCA1/2-mutated cancers.
Recently, we found that acquired platinum resistance can be mediated by secondary mutations in BRCA1/2 that restore the wild-type BRCA1/2 reading frame. In vitro cisplatin selection of two BRCA2-mutated cancer cell lines (a pancreatic cancer cell line, Capan-1, and an ovarian cancer cell line, PEO1) led to generation of subclones with secondary BRCA2 mutations that restored the wild-type BRCA2 reading frame. Importantly, all subclones with secondary BRCA2 mutations were cross-resistant to a PARP inhibitor and cisplatin. The restored BRCA2 proteins in these subclones were functional and responsible for the acquired drug resistance. Furthermore, secondary BRCA1/2 mutations were frequently observed in clinical samples of platinum-resistant recurrent ovarian carcinomas occurred in BRCA1/2 mutation carriers.
These findings indicate that restoration of BRCA1/2 by secondary BRCA1/2 mutations can mediate resistance to platinum and PARP inhibitors in BRCA1/2-mutated tumours. Testing for secondary mutations in BRCA1/2-mutated cancers will be clinically important, because tumours with secondary BRCA1/2 mutations are likely to be resistant to both platinum compounds and PARP inhibitors. Our results also suggest that inhibition of BRCA1/2 function can be a strategy to re-sensitize platinum (or PARP inhibitor)-resistant tumour cells to these drugs.
