University of Michigan researchers demonstrate that the molecular glue RPT04402 stabilizes the Protein phosphatase 2A (PP2A) complex to suppress non-small cell lung cancer and aggressive uterine cancer. By restoring PP2A assembly, RPT04402 overcomes resistance to KRAS-targeted therapies like adagrasib and trametinib, delaying drug resistance past 150 days in mouse models. U-M plans clinical trials with SpringWorks Therapeutics and Merck.
Mechanism of PP2A as a tumor suppressor
- ▪University of Michigan researchers found that targeting Protein phosphatase 2A with the molecular glue RPT04402 helps the protein retain its structure to suppress cancer cell growth.
- ▪The inability of Protein phosphatase 2A to assemble properly is commonly observed in lung, uterine, prostate, and liver cancers.
- ▪Protein phosphatase 2A controls cell signaling pathways and requires three constituent proteins to bind together to function properly as a tumor suppressor.
Non-small cell lung cancer background and KRAS mutations
- ▪Non-small cell lung cancer accounts for over 80% of lung cancers, which represent the second most common cancer and leading cause of cancer death in the United States.
- ▪KRAS gene mutations occur in 30% of non-small cell lung cancer cases, contributing to shorter patient survival times and therapy resistance.
Efficacy of RPT04402 in NSCLC models
- ▪A study published in The Journal of Clinical Investigation by University of Michigan researchers indicated RPT04402 could represent a treatment approach for up to 20% to 30% of non-small cell lung cancers.
- ▪Combining adagrasib or trametinib with RPT04402 delayed drug resistance and increased treatment effectiveness to over 150 days in mouse models of non-small cell lung cancer.
- ▪In non-small cell lung cancer mouse models, University of Michigan researchers confirmed that the molecular glue RPT04402 caused tumors to shrink.
- ▪In non-small cell lung cancer cell lines with KRAS mutations, the anticancer drugs adagrasib and trametinib destabilized PP2A, while adding RPT04402 stabilized the complex and induced cancer cell death.
Uterine cancer characteristics and PP2A mutations
- ▪Recurrent PP2A mutations drive the development of high-grade uterine cancer, which frequently fails to respond or recurs after standard surgery and immunotherapy.
- ▪Uterine cancer is the most common cancer of the female reproductive system and deadliest gynecological malignancy, driven by rising incidence and mortality rates of aggressive high-grade types.
Future clinical trials and expanded applications
- ▪University of Michigan researchers plan to initiate clinical trials evaluating RPT04402 in collaboration with SpringWorks Therapeutics and Merck.
- ▪Researchers aim to evaluate RPT04402 combinations in other KRAS-mutant tumors like pancreatic and colon cancers, as well as neurodevelopmental disorders harboring PP2A mutations.
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