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

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.

Combinatorial nanococktails via self-assembling lipid prodrugs for synergistically overcoming drug resistance and effective cancer therapy

“…4 A). Moreover, Rad51 overexpression and p53 inactivation are responsible for the drug-resistance phenotype [ 49 , 50 ]. Differences were indeed observed between A549 and A549 cisR cells (Fig.…”

PLK1 inhibition selectively kills ARID1A deficient cells through uncoupling of oxygen consumption from ATP production

“…7C). We have previously used a “nuclear expression score” (31) as an overall assessment of a given protein per case, which is reflective of the average intensity of a given protein across all imaged cells. We similarly established an ARID1A nuclear expression score (ARID1A NES ) as a starting point for this assay.…”

Therapy resistance on the RADar in ovarian cancer

“…RAD51 acts as a central recombinase in HR that is important for homology search and strand exchange (Baumann & West, 1998). Hoppe et al (2021) now demonstrate that RAD51 overexpression correlates with platinum resistance in a subset of HGSOC patients.…”

“…Therapy resistance and the selection of effective therapies for patients remains a major challenge. In this issue of EMBO Molecular Medicine, Hoppe et al present RAD51 expression as a biomarker of platinum resistance in high-grade serous ovarian cancer (HGSOC) patients (Hoppe et al, 2021). EMBO Mol Med (2021) 13: e14010…”