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Title: Characterization of a RAD51C-silenced high-grade serous ovarian cancer model during development of PARP inhibitor resistance.
Austin Authors: Hurley, Rachel M;McGehee, Cordelia D;Nesic, Ksenija;Correia, Cristina;Weiskittel, Taylor M;Kelly, Rebecca L;Venkatachalam, Annapoorna;Hou, Xiaonan;Pathoulas, Nicholas M;Meng, X Wei;Kondrashova, Olga;Radke, Marc R;Schneider, Paula A;Flatten, Karen S;Peterson, Kevin L;Becker, Marc A;Wong, Ee Ming;Southey, Melissa S;Dobrovic, Alexander ;Lin, Kevin K;Harding, Thomas C;McNeish, Iain;Ross, Christian A;Wagner, Jill M;Wakefield, Matthew J;Scott, Clare L;Haluska, Paul;Wahner Hendrickson, Andrea E;Karnitz, Larry M;Swisher, Elizabeth M;Li, Hu;Weroha, S John;Kaufmann, Scott H
Affiliation: Division of Cancer, Department of Surgery and Cancer, Imperial College London, Hammersmith Campus, London, W12 0NN United Kingdom
Division of Oncology Research, Mayo Clinic, Rochester, MN 55905 USA
Department of Obstetrics & Gynecology, University of Washington, Seattle, WA 98195, USA
Clovis Oncology, San Francisco, CA 94158, USA
Division of Information Technology, Mayo Clinic, Rochester, MN 55905, USA
The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria 3052, Australia
Precision Medicine, School of Clinical Sciences at Monash Health, Monash University, Victoria 3800, Australia
Surgery (University of Melbourne)
Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, MN 55905 USA
Division of Medical Oncology, Mayo Clinic, Rochester, MN 55905 USA
Issue Date: Sep-2021
Date: 2021
Publication information: NAR Cancer 2021; 3(3): zcab028
Abstract: Acquired PARP inhibitor (PARPi) resistance in BRCA1- or BRCA2-mutant ovarian cancer often results from secondary mutations that restore expression of functional protein. RAD51C is a less commonly studied ovarian cancer susceptibility gene whose promoter is sometimes methylated, leading to homologous recombination (HR) deficiency and PARPi sensitivity. For this study, the PARPi-sensitive patient-derived ovarian cancer xenograft PH039, which lacks HR gene mutations but harbors RAD51C promoter methylation, was selected for PARPi resistance by cyclical niraparib treatment in vivo. PH039 acquired PARPi resistance by the third treatment cycle and grew through subsequent treatment with either niraparib or rucaparib. Transcriptional profiling throughout the course of resistance development showed widespread pathway level changes along with a marked increase in RAD51C mRNA, which reflected loss of RAD51C promoter methylation. Analysis of ovarian cancer samples from the ARIEL2 Part 1 clinical trial of rucaparib monotherapy likewise indicated an association between loss of RAD51C methylation prior to on-study biopsy and limited response. Interestingly, the PARPi resistant PH039 model remained platinum sensitive. Collectively, these results not only indicate that PARPi treatment pressure can reverse RAD51C methylation and restore RAD51C expression, but also provide a model for studying the clinical observation that PARPi and platinum sensitivity are sometimes dissociated.
DOI: 10.1093/narcan/zcab028
ORCID: 0000-0003-3414-112X
Journal: NAR Cancer
PubMed URL: 34316715
Type: Journal Article
Subjects: Ovarian cancer
Appears in Collections:Journal articles

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