期刊
EMBO MOLECULAR MEDICINE
卷 13, 期 5, 页码 -出版社
WILEY
DOI: 10.15252/emmm.202013366
关键词
HRD; immune exclusion; multiplexed IHC; ovarian cancer; RAD51
资金
- Cancer Science Institute of Singapore
- National University of Singapore PhD Graduate Scholarship
- Singapore Ministry of Health's National Medical Research Council Transition Award [NMRC/TA/0052/2016]
- National Research Foundation Singapore
- Singapore Ministry of Education under its Research Centres of Excellence initiative
- Singapore Ministry of Health's National Medical Research Council Individual Research Grant [NMRC/CIRG/1400/2014]
- Singapore Ministry of Health's National Medical Research Council Clinician Scientist Award [NMRC/CSA-INV/0016/2017]
- CRUK Imperial Centre
- Imperial Experimental Medicine Centre (SCOTROC4 TMA construction)
- Cancer Research UK
- Ovarian Cancer Action
The study showed that high RAD51 expression in epithelial ovarian cancer is associated with shorter progression-free and overall survival, as well as platinum resistance, especially in HR-proficient cancers. RAD51 overexpression may also modify the expression of immune-regulatory pathways and result in exclusion of cytotoxic T cells in situ.
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.
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