Quantitative imaging of RAD51 expression as a marker of platinum resistance in ovarian cancer

Hoppe, MM; Jaynes, P; Wardyn, JD; Upadhyayula, SS; Tan, TZ; Lie, S; Lim, DGZ; Pang, BNK; Lim, S; PSYeong J; Karnezis, A; Chiu, DS; Leung, S; Huntsman, DG; Sedukhina, AS; Sato, K; Topp, MD; Scott, CL; Choi, H; Patel, NR; Brown, R; Kaye, SB; Pitt, JJ; Tan, DSP; Jeyasekharan, AD

Author(s): Hoppe, MM; Jaynes, P; Wardyn, JD; Upadhyayula, SS; Tan, TZ; Lie, S; Lim, DGZ; Pang, BNK; Lim, S; PSYeong J; Karnezis, A; Chiu, DS; Leung, S; Huntsman, DG; Sedukhina, AS; Sato, K; Topp, MD; Scott, CL; Choi, H; Patel, NR; Brown, R; Kaye, SB; Pitt, JJ; Tan, DSP; Jeyasekharan, AD;
Details: Publication Year 2021-03-11,Volume 13,Issue #5,Page e13366
Journal Title: EMBO Molecular Medicine
Abstract: Early relapse after platinum chemotherapy in epithelial ovarian cancer (EOC) portends poor survival. A-priori identification of platinum resistance is therefore crucial to improve on standard first-line carboplatin-paclitaxel treatment. The DNA repair pathway homologous recombination (HR) repairs platinum-induced damage, and the HR recombinase RAD51 is overexpressed in cancer. We therefore designed a REMARK-compliant study of pre-treatment RAD51 expression in EOC, using fluorescent quantitative immunohistochemistry (qIHC) to overcome challenges in quantitation of protein expression in situ. In a discovery cohort (n = 284), RAD51-High tumours had shorter progression-free and overall survival compared to RAD51-Low cases in univariate and multivariate analyses. The association of RAD51 with relapse/survival was validated in a carboplatin monotherapy SCOTROC4 clinical trial cohort (n = 264) and was predominantly noted in HR-proficient cancers (Myriad HRDscore < 42). Interestingly, overexpression of RAD51 modified expression of immune-regulatory pathways in vitro, while RAD51-High tumours showed exclusion of cytotoxic T cells in situ. Our findings highlight RAD51 expression as a determinant of platinum resistance and suggest possible roles for therapy to overcome immune exclusion in RAD51-High EOC. The qIHC approach is generalizable to other proteins with a continuum instead of discrete/bimodal expression.
Publisher: Embo Press
Keywords: Hrd; Rad51; immune exclusion; multiplexed IHC; ovarian cancer
Research Division(s): Cancer Biology And Stem Cells
PubMed ID: 33709473
Publisher's Version: https://doi.org/10.15252/emmm.202013366
Open Access at Publisher's Site: https://doi.org/10.15252/emmm.202013366
Terms of Use/Rights Notice: Refer to copyright notice on published article.
Documents: emmm.202013366.pdf - (1.14MB, application/pdf)

Creation Date: 2021-03-26 10:28:26

Last Modified: 2021-07-07 11:56:56