Secondary Somatic Mutations Restoring RAD51C and RAD51D Associated with Acquired Resistance to the PARP Inhibitor Rucaparib in High-grade Ovarian Carcinoma. Cancer discovery Kondrashova, O., Nguyen, M., Shield-Artin, K., Tinker, A. V., Teng, N. N., Harrell, M. I., Kuiper, M. J., Ho, G., Barker, H., Jasin, M., Prakash, R., Kass, E. M., Sullivan, M. R., Brunette, G. J., Bernstein, K. A., Coleman, R. L., Floquet, A., Friedlander, M., Kichenadasse, G., O'Malley, D. M., Oza, A. M., Sun, J. X., Robillard, L., Maloney, L., Bowtell, D. D., Giordano, H., Wakefield, M. J., Kaufmann, S. H., Simmons, A. D., Harding, T. C., Raponi, M., McNeish, I. A., Swisher, E. M., Lin, K., Scott, C. L. 2017


High-grade epithelial ovarian carcinomas (OC) containing mutated BRCA1 or BRCA2 (BRCA1/2) homologous recombination (HR) genes are sensitive to platinum-based chemotherapy and poly(ADP-ribose) polymerase inhibitors (PARPi), while restoration of HR function due to secondary mutations in BRCA1/2 has been recognized as an important resistance mechanism. We sequenced core HR pathway genes in 12 pairs of pre-treatment and post-progression tumor biopsy samples collected from patients in ARIEL2 Part 1, a phase 2 study of the PARPi rucaparib as treatment for platinum-sensitive, relapsed OC. In six of 12 pre-treatment biopsies, a truncation mutation in BRCA1, RAD51C or RAD51D was identified. In five of six paired post-progression biopsies, one or more secondary mutations restored the open reading frame. Four distinct secondary mutations and spatial heterogeneity were observed for RAD51C. In vitro complementation assays and a patient-derived xenograft (PDX), as well as predictive molecular modeling, confirmed that resistance to rucaparib was associated with secondary mutations.

View details for DOI 10.1158/2159-8290.CD-17-0419

View details for PubMedID 28588062