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

2021-09

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

Ovarian cancer

Journal Article

0000-0003-3414-112X

0000-0002-4900-7145

10.1093/narcan/zcab028

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.

link

NAR Cancer 2021; 3(3): zcab028

NAR Cancer