Mes/Stem-A ovarian cancer subtypes predict sensitivity to ATR inhibition.

High-grade serous ovarian cancer (HGSOC) remains one of the most common and lethal gynecological malignancies. Distinct gene expression molecular subtypes (GEMS) of HGSOC, with associated differences in outcome, have previously been described: Epithelial-A (Epi-A)/C3/Differentiated, Epithelial-B (Epi-B)/C2/Immunoreactive, Stem-like B (Stem-B)/C6, Mesenchymal (Mes)/C1, and Stem-like A (Stem-A)/C5/Proliferative. Notably, the Mes and Stem-A OC subtypes are associated with more advanced-stage tumors and poorer clinical outcomes, representing a molecular subtype of unmet clinical need. Hallmarks of HGSOC also include a high prevalence of genomic instability and increased replication stress. In this study, we demonstrate that HGSOC Mes/Stem-A (MSA) cell lines exhibit elevated levels of replication stress and increased sensitivity to ATR inhibitors. Additionally, through DNA fiber analysis, we observed significantly higher replication fork rates and ssDNA accumulation in MSA subtype cells. Consistent with the high levels of replication stress identified in these subtypes, MSA patient-derived xenograft models further validated the therapeutic vulnerability to ATR inhibition. The characteristic replication stress profile of the MSA subtype suggests its utility as a candidate biomarker for identifying patients most likely to benefit from ATR inhibition.