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

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

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    “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.


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