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

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posted on 11.10.2021, 23:13 by Rachel M Hurley, Cordelia D McGehee, Ksenija Nesic, Cristina Correia, Taylor M Weiskittel, Rebecca L Kelly, Annapoorna Venkatachalam, Xiaonan Hou, Nicholas M Pathoulas, X Wei Meng, Olga Kondrashova, Marc R Radke, Paula A Schneider, Karen S Flatten, Kevin L Peterson, Marc A Becker, Ee Ming Wong, Melissa S Southey, Alexander DobrovicAlexander Dobrovic, Kevin K Lin, Thomas C Harding, Iain McNeish, Christian A Ross, Jill M Wagner, Matthew J Wakefield, Clare L Scott, Paul Haluska, Andrea E Wahner Hendrickson, Larry M Karnitz, Elizabeth M Swisher, Hu Li, S John Weroha, Scott H Kaufmann
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.

Funding

National Institutes of Health [P50 CA136393, F30 CA213737, T32 GM072474, T32 GM085641]; Ovarian Cancer Research Alliance (to E.M.S., P.H., S.H.K.); Stand Up to Cancer [SU2C-AACR-DT16-15] (to A.E.W.H., E.M.S., S.J.W., S.H.K.); Stafford Fox Medical Research Foundation (to C.L.S., O.K., M.W., K.N.); National Breast Cancer Foundation of Australia (to A.D.); Mayo Foundation for Education and Research (to R.M.H., C.D.M., T.M., R.L.K., A.V.)

History

Publication Date

01/09/2021

Journal

NAR Cancer

Volume

3

Issue

3

Article Number

zcab028

Pagination

13p.

Publisher

Oxford University Press

ISSN

2632-8674

Rights Statement

The Author reserves all moral rights over the deposited text and must be credited if any re-use occurs. Documents deposited in OPAL are the Open Access versions of outputs published elsewhere. Changes resulting from the publishing process may therefore not be reflected in this document. The final published version may be obtained via the publisher’s DOI. Please note that additional copyright and access restrictions may apply to the published version.

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