Secondary Somatic Mutations Restoring RAD51C and RAD51D Associated with Acquired Resistance to the PARP Inhibitor Rucaparib in High-Grade Ovarian Carcinoma
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)
polymeraseinhibitors (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
rucaparibas treatment for platinum-sensitive, relapsed OC. In six of 12 pre-treatment biopsies, a truncation mutation in BRCA1,
RAD51Cor 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 heterogeneitywere observed for
RAD51C. In vitro complementation assays and a patient-derived xenograft (PDX), as well as predictive molecular modeling, confirmed that resistance to
rucaparibwas associated with secondary mutations.
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