Characterization of a RAD51C-silenced high-grade serous ovarian cancer model during development of PARP inhibitor resistance

Author:

Hurley Rachel M1,McGehee Cordelia D1,Nesic Ksenija23,Correia Cristina14,Weiskittel Taylor M1,Kelly Rebecca L1,Venkatachalam Annapoorna1,Hou Xiaonan5,Pathoulas Nicholas M4,Meng X Wei14,Kondrashova Olga23,Radke Marc R6,Schneider Paula A4,Flatten Karen S4,Peterson Kevin L4,Becker Marc A5,Wong Ee Ming78,Southey Melissa S789,Dobrovic Alexander10ORCID,Lin Kevin K11,Harding Thomas C11,McNeish Iain12,Ross Christian A13,Wagner Jill M5,Wakefield Matthew J214,Scott Clare L2314,Haluska Paul5,Wahner Hendrickson Andrea E5,Karnitz Larry M14,Swisher Elizabeth M6,Li Hu115,Weroha S John5,Kaufmann Scott H14ORCID

Affiliation:

1. Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, MN 55905 USA

2. The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria 3052, Australia

3. Department of Medical Biology, University of Melbourne, Parkville, Victoria 3010, Australia

4. Division of Oncology Research, Mayo Clinic, Rochester, MN 55905 USA

5. Division of Medical Oncology, Mayo Clinic, Rochester, MN 55905 USA

6. Department of Obstetrics & Gynecology, University of Washington, Seattle, WA 98195, USA

7. Precision Medicine, School of Clinical Sciences at Monash Health, Monash University, Victoria 3800, Australia

8. Department of Clinical Pathology, Melbourne Medical School, The University of Melbourne, Parkville, Victoria 3000, Australia

9. Cancer Epidemiology Division, Cancer Council Victoria, Melbourne, Victoria 3004, Australia

10. University of Melbourne Department of Surgery, Austin Hospital, Heidelberg, Victoria 3084, Australia

11. Clovis Oncology, San Francisco, CA 94158, USA

12. Division of Cancer, Department of Surgery and Cancer, Imperial College London, Hammersmith Campus, London, W12 0NN United Kingdom

13. Division of Information Technology, Mayo Clinic, Rochester, MN 55905, USA

14. Department of Obstetrics and Gynaecology, University of Melbourne, Parkville, Victoria 3052, Australia

15. Center for Individualized Medicine, Mayo Clinic, Rochester, MN 55905 USA

Abstract

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.

Funder

National Institutes of Health

Ovarian Cancer Research Alliance

Stand Up To Cancer

Stafford Fox Medical Research Foundation

National Breast Cancer Foundation

Mayo Foundation for Education and Research

Publisher

Oxford University Press (OUP)

Subject

General Medicine

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