2. Academic Validation
  3. Secondary Somatic Mutations Restoring RAD51C and RAD51D Associated with Acquired Resistance to the PARP Inhibitor Rucaparib in High-Grade Ovarian Carcinoma

Secondary Somatic Mutations Restoring RAD51C and RAD51D Associated with Acquired Resistance to the PARP Inhibitor Rucaparib in High-Grade Ovarian Carcinoma

  • Cancer Discov. 2017 Sep;7(9):984-998. doi: 10.1158/2159-8290.CD-17-0419.
Olga Kondrashova 1 2,  Minh Nguyen 3,  Kristy Shield-Artin 1 2,  Anna V Tinker 4,  Nelson N H Teng 5,  Maria I Harrell 6,  Michael J Kuiper 7,  Gwo-Yaw Ho 1 2 8,  Holly Barker 1 2,  Maria Jasin 9,  Rohit Prakash 9,  Elizabeth M Kass 9,  Meghan R Sullivan 10,  Gregory J Brunette 10,  Kara A Bernstein 10,  Robert L Coleman 11,  Anne Floquet 12,  Michael Friedlander 13,  Ganessan Kichenadasse 14,  David M O'Malley 15,  Amit Oza 16,  James Sun 17,  Liliane Robillard 3,  Lara Maloney 3,  David Bowtell,  Heidi Giordano 3,  Matthew J Wakefield 1 7,  Scott H Kaufmann 18,  Andrew D Simmons 3,  Thomas C Harding 3,  Mitch Raponi 3,  Iain A McNeish 19,  Elizabeth M Swisher 6,  Kevin K Lin 3,  Clare L Scott 20 2 8,  AOCS Study Group
Affiliations

Affiliations

  • 1 Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria, Australia.
  • 2 Department of Medical Biology, The University of Melbourne, Melbourne, Victoria, Australia.
  • 3 Clovis Oncology, Inc., Boulder, Colorado.
  • 4 British Columbia Cancer Agency, Vancouver, British Columbia, Canada.
  • 5 Stanford University, Palo Alto, California.
  • 6 University of Washington, Seattle, Washington.
  • 7 Melbourne Bioinformatics, The University of Melbourne, Melbourne, Victoria, Australia.
  • 8 Department of Medical Oncology, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.
  • 9 Developmental Biology Program, Memorial Sloan Kettering Cancer Center, New York, New York.
  • 10 Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania.
  • 11 The University of Texas MD Anderson Cancer Center, Houston, Texas.
  • 12 Institut Bergonié, Bordeaux, France.
  • 13 University of New South Wales and Prince of Wales Hospital, Sydney, New South Wales, Australia.
  • 14 Flinders University, Adelaide, South Australia, Australia.
  • 15 The Ohio State University, James Cancer Center, Columbus, Ohio.
  • 16 Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada.
  • 17 Foundation Medicine, Inc., Cambridge, Massachusetts.
  • 18 Mayo Clinic Cancer Center, Rochester, Minnesota.
  • 19 Institute of Cancer Sciences, University of Glasgow, Glasgow, United Kingdom.
  • 20 Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria, Australia. [email protected].
PMID: 28588062 DOI: 10.1158/2159-8290.CD-17-0419
Abstract

High-grade epithelial ovarian carcinomas containing mutated BRCA1 or BRCA2 (BRCA1/2) homologous recombination (HR) genes are sensitive to platinum-based chemotherapy and PARP 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 pretreatment and postprogression tumor biopsy samples collected from patients in ARIEL2 Part 1, a phase II study of the PARPi rucaparib as treatment for platinum-sensitive, relapsed ovarian carcinoma. In 6 of 12 pretreatment biopsies, a truncation mutation in BRCA1, RAD51C, or RAD51D was identified. In five of six paired postprogression biopsies, one or more secondary mutations restored the open reading frame. Four distinct secondary mutations and spatial heterogeneity were observed for RAD51CIn vitro complementation assays and a patient-derived xenograft, as well as predictive molecular modeling, confirmed that resistance to rucaparib was associated with secondary mutations.Significance: Analyses of primary and secondary mutations in RAD51C and RAD51D provide evidence for these primary mutations in conferring PARPi sensitivity and secondary mutations as a mechanism of acquired PARPi resistance. PARPi resistance due to secondary mutations underpins the need for early delivery of PARPi therapy and for combination strategies. Cancer Discov; 7(9); 984-98. ©2017 AACR.See related commentary by Domchek, p. 937See related article by Quigley et al., p. 999See related article by Goodall et al., p. 1006This article is highlighted in the In This Issue feature, p. 920.

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