Research conducted by Dr. Ou Deng at Moffitt Cancer Center highlights the role of MSH6 in influencing the effectiveness of PARP inhibitors for patients diagnosed with BRCA-proficient high-grade serous ovarian cancer (HGSOC). During the 2025 AACR Annual Meeting, Dr. Deng and her colleagues unveiled findings that delve into the underlying mechanisms affecting PARP inhibitor sensitivity in this patient group.
Their preclinical studies indicate that MSH6, a crucial mismatch repair protein, may have an impact on tumor responses that extends beyond its established function in DNA damage repair. This discovery prompts further exploration into MSH6’s potential utility as a biomarker for treatment efficacy.
Investigating MSH6’s Mechanisms
Dr. Deng emphasized the importance of understanding how MSH6 expression regulates various downstream signaling pathways, which could be pivotal in determining sensitivity to PARP inhibitors. “Mapping these downstream processes is critical to understanding how MSH6 contributes to treatment resistance or responsiveness,” she explained.
The research team is planning translational studies to assess the correlation between MSH6 expression levels and clinical outcomes in patients with BRCA-proficient ovarian cancer undergoing PARP inhibitor therapy. This particular subgroup typically sees limited benefits from such treatments. Establishing MSH6 as a predictive biomarker could significantly enhance patient selection for PARP inhibitor therapies, thereby broadening the scope of their effectiveness.
Future Research Directions
To facilitate these investigations, Dr. Deng and her team aim to employ immunohistochemistry and other assays on tumor samples from patients treated with PARP inhibitors. These analyses will explore whether the levels of MSH6 correspond to clinical responses, ultimately linking molecular findings to patient outcomes.
“The ultimate objective of this research is to establish MSH6 as a clinically actionable biomarker, identifying patients with BRCA-proficient disease who are most likely to respond to PARP inhibition,” Dr. Deng stated. By refining the criteria for patient selection, this research could lead to more personalized and effective treatment approaches for those affected by high-grade serous ovarian cancer.