Ou Deng, PhD, is a research scientist at Moffitt Cancer Center

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 

-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 

-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 

-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 

-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 

-proficient disease who are most likely to respond to PARP inhibition.

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Ou Deng, PhD, discusses research aimed at clarifying the role of MSH6 in modulating sensitivity to PARP inhibitors in patients with BRCA-proficient HGSOC

Dr Deng on the Effects of MSH6 on PARP Inhibitor Sensitivity in Ovarian Cancer

“MSH6 actually modulates PARP inhibitor sensitivity, and MSH6 also regulates CHAF1A expression. We have [shown that] MSH6 modulates sensitivity through regulation of CHAF1A, [which reports have shown that] when knocked down, causes a very lethal effect for the majority of the cells.”

Ou Deng, PhD, a research scientist at Moffitt Cancer Center, discussed findings from a study investigating ways that MSH6 levels modulate PARP inhibitor sensitivity in BRCA-proficient, high-grade serous ovarian cancer.

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, high-grade serous ovarian cancer. The investigators hypothesized that the composition of the PARP1 protein complex and PARylation-mediated signaling regulate PARP inhibitor resistance and sensitivity in this disease subset. The investigators performed viability screening of BRCA-proficient ovarian cancer cell lines that had been treated with PARP inhibitors. From there, they identified 3 resistant and 3 sensitive lines.

A chemical proteomics analysis found different PARP1 interactions between PARP inhibitor–sensitive and PARP inhibitor–resistant cell lines, according to Deng. Additionally, an ADP-ribosylation analysis showed distinct PARylation profiles between sensitive and resistant cell lines. Levels of PARP1, PARP2, associated binding proteins, and MSH6 were enriched in the sensitive lines but not the resistant lines. Co-immunoprecipitation also showed differences between the compositions of the PARP1-MSH6-PARP2 complex of the resistant and sensitive lines. Genetic knockout of MSH6 conferred resistance to the PARP inhibitor rucaparib (Rubraca); this effect was more pronounced in the PARP inhibitor–sensitive cells.

Furthermore, the known MSH6 binder CHAF1A, which is also a PARP1 substrate, was seen in the sensitive cells. Moreover, the investigators observed interactions between MSH6 and CHAF1A. MSH6 knockdown elevated the levels of CHAF1A observed in the sensitive cells, conferring PARP inhibitor resistance, Deng explained. Therefore, MSH6 modulates cell sensitivity to PARP inhibitors and regulates CHAF1A expression, she noted. Prior reports have shown that CHAF1A knockdown is lethal to cells, she concluded.

Ou Deng, PhD, discussed findings from a study investigating MSH6-modulated PARP inhibitor sensitivity in BRCA-proficient, high-grade serous ovarian cancer.

Ou Deng, PhD

Articles

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

Dr Deng on the Effects of MSH6 on PARP Inhibitor Sensitivity in Ovarian Cancer