Phospho-RPA2 predicts response to platinum and PARP inhibitors in homologous recombination–proficient ovarian cancer

作者：Angela M. Schab, Amanda Compadre, Rebecca Drexler, Megan Loeb, Kevin Rodriguez, Joshua Brill, Shariska P. Harrington, Carmen Sandoval, Brooke E. Sanders, Lindsay M. Kuroki, Carolyn K. McCourt, Andrea R. Hagemann, Premal H. Thaker, David G. Mutch, Matthew A. Powell, Violeta Serra, Ian S. Hagemann, Ann E. Walts, Beth Karlan, Sandra Oršulić, Katherine C. Fuh, Lulu Sun, Priyanka Verma, Elena Lomonosova, Peinan Zhao, Dineo Khabele, Mary M. Mullen · 发表于：Journal of Clinical Investigation · 年份：2025 · DOI：10.1172/jci189511 · 被引用次数：7 · 研究领域：Advanced Electron Microscopy Techniques and Applications、Electron and X-Ray Spectroscopy Techniques、Advanced biosensing and bioanalysis techniques

BACKGROUNDTreatment of tubo-ovarian high-grade serous carcinoma (HGSC) includes cytoreductive surgery, platinum-based chemotherapy, and often poly(ADP-ribose) polymerase (PARP) inhibitors. While homologous recombination (HR) deficiency is a well-established predictor of therapy sensitivity, over 50% of HR-proficient HGSCs also exhibit sensitivity. Currently, there are no biomarkers to identify which HR-proficient HGSCs will be sensitive to standard-of-care therapy. Replication stress may serve as a key determinant of response.METHODSWe evaluated phospho-RPA2-T21 (p-RPA2) foci via immunofluorescence as a biomarker of replication stress in formalin-fixed, paraffin-embedded HGSC samples collected at diagnosis from patients treated with platinum chemotherapy (discovery cohort, n = 31; validation cohort, n = 244) or PARP inhibitors (n = 63). Recurrent HGSCs (n = 38) were also analyzed. p-RPA2 score was calculated using automated imaging analysis.RESULTSSamples were defined as p-RPA2-high if more than 16% of cells had ≥2 p-RPA2 foci on automated analysis. In the discovery cohort, HR-proficient, p-RPA2-high HGSCs demonstrated significantly higher rates of a chemotherapy response score of 3 to platinum chemotherapy than HR-proficient, p-RPA2-low HGSCs. In the validation cohort, patients with HR-proficient, p-RPA2-high HGSCs had significantly longer survival after platinum treatment than those with HR-proficient, p-RPA2-low HGSCs. Additionally, the p-RPA2 assay effectively predicted s...