Dr Deng on the Role of MSH6 in Modulating PARP Inhibitor Sensitivity in BRCA-Proficient High-Grade Serous Ovarian Cancer

“We hope that MSH6 could serve as a biomarker to identify BRCA-proficient patients who are more likely to respond to PARP therapy."

Ou Deng, PhD, a research scientist at Moffitt Cancer Center, discussed future research efforts aimed at clarifying the role of MSH6 in modulating sensitivity to PARP inhibitors in patients with BRCA-proficient high-grade serous ovarian cancer (HGSOC).

At the 2025 AACR Annual Meeting, Deng and colleagues presented research that revealed some of the mechanisms that drive PARP inhibitor sensitivity in BRCA-proficient HGSOC. Preclinical observations suggest that MSH6, a mismatch repair protein, may influence tumor response beyond its canonical role in DNA damage repair, prompting further investigation into its potential as a biomarker of treatment benefit.

Ongoing laboratory studies will evaluate how MSH6 expression regulates downstream signaling pathways beyond DNA repair, as these molecular mechanisms may play a role in determining PARP inhibitor sensitivity, Deng began. According to Deng, mapping these downstream processes is critical to understanding how MSH6 contributes to treatment resistance or responsiveness.

Planned translational research includes analyzing correlations between MSH6 expression levels and clinical outcomes among patients with BRCA-proficient ovarian cancer who receive PARP inhibitors, Deng said. Since this patient subgroup typically experiences limited benefit from PARP inhibition, validating MSH6 as a predictive biomarker could refine patient selection for this class of treatment and expand the therapeutic reach of these agents.

To advance these efforts, Deng and colleagues intend to conduct immunohistochemistry and other assays on tumor samples from patients treated with PARP inhibitors. These analyses will assess whether MSH6 levels align with clinical responses, thereby linking molecular findings to patient outcomes, she explained. According to Deng, the ultimate objective of this research is to establish MSH6 as a clinically actionable biomarker to identify the patients with BRCA-proficient disease who are most likely to respond to PARP inhibition.