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

Michal M. Hoppe, Patrick Jaynes, Joanna D. Wardyn, Sai Srinivas Upadhyayula, Tuan Zea Tan, Stefanus Lie, Diana G.Z. Lim, Brendan N.K. Pang, Sherlly Lim, Joe P S Yeong, Anthony Karnezis, Derek S. Chiu, Samuel Leung, David G. Huntsman, Anna S. Sedukhina, Ko Sato, Monique D. Topp, Clare L. Scott, Hyungwon Choi, Naina R. PatelRobert Brown, Stan B. Kaye, Jason J. Pitt, David S.P. Tan, Anand D. Jeyasekharan

Research output: Contribution to journalArticlepeer-review

2 Scopus citations

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.

Original languageEnglish (US)
Article numbere13366
JournalEMBO Molecular Medicine
Volume13
Issue number5
DOIs
StatePublished - May 7 2021

Keywords

  • HRD
  • immune exclusion
  • multiplexed IHC
  • ovarian cancer
  • RAD51

ASJC Scopus subject areas

  • Molecular Medicine

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