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

Autor:	Kondrashova O; Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria, Australia.; Department of Medical Biology, The University of Melbourne, Melbourne, Victoria, Australia., Nguyen M; Clovis Oncology, Inc., Boulder, Colorado., Shield-Artin K; Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria, Australia.; Department of Medical Biology, The University of Melbourne, Melbourne, Victoria, Australia., Tinker AV; British Columbia Cancer Agency, Vancouver, British Columbia, Canada., Teng NNH; Stanford University, Palo Alto, California., Harrell MI; University of Washington, Seattle, Washington., Kuiper MJ; Melbourne Bioinformatics, The University of Melbourne, Melbourne, Victoria, Australia., Ho GY; Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria, Australia.; Department of Medical Biology, The University of Melbourne, Melbourne, Victoria, Australia.; Department of Medical Oncology, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia., Barker H; Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria, Australia.; Department of Medical Biology, The University of Melbourne, Melbourne, Victoria, Australia., Jasin M; Developmental Biology Program, Memorial Sloan Kettering Cancer Center, New York, New York., Prakash R; Developmental Biology Program, Memorial Sloan Kettering Cancer Center, New York, New York., Kass EM; Developmental Biology Program, Memorial Sloan Kettering Cancer Center, New York, New York., Sullivan MR; Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania., Brunette GJ; Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania., Bernstein KA; Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania., Coleman RL; The University of Texas MD Anderson Cancer Center, Houston, Texas., Floquet A; Institut Bergonié, Bordeaux, France., Friedlander M; University of New South Wales and Prince of Wales Hospital, Sydney, New South Wales, Australia., Kichenadasse G; Flinders University, Adelaide, South Australia, Australia., O'Malley DM; The Ohio State University, James Cancer Center, Columbus, Ohio., Oza A; Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada., Sun J; Foundation Medicine, Inc., Cambridge, Massachusetts., Robillard L; Clovis Oncology, Inc., Boulder, Colorado., Maloney L; Clovis Oncology, Inc., Boulder, Colorado., Bowtell D, Giordano H; Clovis Oncology, Inc., Boulder, Colorado., Wakefield MJ; Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria, Australia.; Melbourne Bioinformatics, The University of Melbourne, Melbourne, Victoria, Australia., Kaufmann SH; Mayo Clinic Cancer Center, Rochester, Minnesota., Simmons AD; Clovis Oncology, Inc., Boulder, Colorado., Harding TC; Clovis Oncology, Inc., Boulder, Colorado., Raponi M; Clovis Oncology, Inc., Boulder, Colorado., McNeish IA; Institute of Cancer Sciences, University of Glasgow, Glasgow, United Kingdom., Swisher EM; University of Washington, Seattle, Washington., Lin KK; Clovis Oncology, Inc., Boulder, Colorado., Scott CL; Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria, Australia. scottc@wehi.edu.au.; Department of Medical Biology, The University of Melbourne, Melbourne, Victoria, Australia.; Department of Medical Oncology, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.
Jazyk:	angličtina
Zdroj:	Cancer discovery [Cancer Discov] 2017 Sep; Vol. 7 (9), pp. 984-998. Date of Electronic Publication: 2017 Jun 06.
DOI:	10.1158/2159-8290.CD-17-0419
Abstrakt:	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 RAD51C In 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. 937 See related article by Quigley et al., p. 999 See related article by Goodall et al., p. 1006 This article is highlighted in the In This Issue feature, p. 920 . (©2017 American Association for Cancer Research.)
Databáze:	MEDLINE
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