Notice: Users may be experiencing issues with displaying some pages on stanfordhealthcare.org. We are working closely with our technical teams to resolve the issue as quickly as possible. Thank you for your patience.
 

Learn about the flu shot, COVID-19 vaccine, and our masking policy »

Stanford Health Care

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

Abstract

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