Journal article

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

Olga Kondrashova, Minh Nguyen, Kristy Shield-Artin, Anna V Tinker, Nelson NH Teng, Maria I Harrell, Michael J Kuiper, Gwo-Yaw Ho, Holly Barker, Maria Jasin, Rohit Prakash, Elizabeth M Kass, Meghan R Sullivan, Gregory J Brunette, Kara A Bernstein, Robert L Coleman, Anne Floquet, Michael Friedlander, Ganessan Kichenadasse, David M O'Malley Show all

CANCER DISCOVERY | AMER ASSOC CANCER RESEARCH | Published : 2017

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 pos..

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Grants

Awarded by National Health and Medical Research Council (NHMRC Australia)


Awarded by Victorian Cancer Agency


Awarded by National Institutes of Health


Awarded by Stand Up To Cancer Innovative Research Grant


Awarded by NIH


Awarded by MSK Cancer Center Support Grant/Core Grant


Awarded by Stand Up To Cancer-Ovarian Cancer Research Fund-Ovarian Cancer National Alliance-National Ovarian Cancer Coalition Dream Team Translational Research Grant


Awarded by Victorian Life Sciences Computation Initiative


Awarded by U. S. Army Medical Research and Materiel Command


Awarded by National Health and Medical Research Council of Australia (NHMRC)


Awarded by NATIONAL CANCER INSTITUTE


Awarded by NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES


Awarded by NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES


Funding Acknowledgements

This work was supported by fellowships and grants from the National Health and Medical Research Council (NHMRC Australia; Project grant 1062702 to C.L. Scott); the Cancer Council Victoria (Sir Edward Dunlop Fellowship in Cancer Research to C.L. Scott); the Victorian Cancer Agency (Clinical Fellowships CRF10-20 and CRF16014 to C.L. Scott); CRC for Cancer Therapeutics (PhD topup scholarship to G.-Y. Ho); the Stafford Fox Medical Research Foundation including a WEHI Centenary Stafford Fox Fellowship to H. Barker; the National Institutes of Health (2P50CA083636 to E.M. Swisher); and the Wendy Feuer Ovarian Cancer Research Fund (to E.M. Swisher). This work was made possible through the Australian Cancer Research Foundation, the Victorian State Government Operational Infrastructure Support and Australian Government NHMRC IRIISS. We thank Clovis Oncology for funding Foundation Medicine's analyses and providing rucaparib for in vivo experiments. K.A. Bernstein is supported by a National Institutes of Health Grant (ES024872), the V Foundation for Cancer Research, and a Stand Up To Cancer Innovative Research Grant (Grant Number SU2C-AACR-IRG-02-16). Stand Up To Cancer is a program of the Entertainment Industry Foundation. Research grants are administered by the American Association for Cancer Research, the Scientific Partner of SU2C. R. Prakash was supported by NIH F32GM110978. M. Jasin is supported by NIH R01CA185660 and the MSK Cancer Center Support Grant/Core Grant (NIH P30CA008748). E. M. Kass, E. M. Swisher, M. Jasin, R. L. Coleman and S. H. Kaufmann are supported by a Stand Up To Cancer-Ovarian Cancer Research Fund-Ovarian Cancer National Alliance-National Ovarian Cancer Coalition Dream Team Translational Research Grant (Grant Number: SU2C-AACR-DT16-15). MD modeling was supported by Victorian Life Sciences Computation Initiative grant LTU0011 on its Peak Computing Facility at the University of Melbourne, an initiative of the Victorian Government, Australia. The Australian Ovarian Cancer Study was supported by the U. S. Army Medical Research and Materiel Command under DAMD17-01-10729, The Cancer Council Tasmania, The Cancer Foundation of Western Australia, and the National Health and Medical Research Council of Australia (NHMRC; ID400413 and ID400281).