Targeting Hotspot PPP2R1A Mutations with Small-Molecule PP2A Activators Induces Tumor Regression

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Summary of  Science Translational Medicine https://doi.org/10.1126/scitranslmed.ady4852
Dr. Irene Peris et al.

Points

University of Michigan researchers investigated small molecule molecular glues designed to correct protein phosphatase 2A assembly defects driven by recurrent scaffolding mutations in high grade uterine cancer.
Experimental assays confirmed that lead molecule RPT04402 promoted regulatory B56alpha subunit heterotrimerization with both Pro179Arg and Ser256Phe mutant protein scaffolds.
In vivo testing across multiple mutant cell lines and patient derived xenografts demonstrated robust single agent antitumor activity resulting in significant tumor regressions and extended median survival.
Specificity analyses proved that the therapeutic efficacy of RPT04402 depended entirely on B56alpha binding as genetic knockout of the subunit completely abolished drug activity.
Authors concluded that restoring heterotrimeric phosphatase complex formation with molecular glues represents a first in class precision medicine strategy for aggressive PPP2R1A mutant gynecological cancers.

Summary

This study evaluated the therapeutic efficacy of RPT04402, a first-in-class small-molecule molecular glue designed to restore protein phosphatase 2A (PP2A) holoenzyme assembly in high-grade endometrial carcinomas. Published in Science Translational Medicine by University of Michigan researchers, the investigation targeted oncogenic heterozygous hotspot mutations in PPP2R1A, which encodes the A-alpha scaffolding subunit of PP2A. Given that recurrent PPP2R1A mutations at Pro179 and Ser256 residues disrupt the binding of tumor-suppressive B56 and B55 regulatory subunits to drive aggressive uterine cancer, the research sought to determine whether structural stabilization of the trimeric complex could restore phosphatase activity and induce tumor regression.

Utilizing a small-molecule library tailored to fit the pocket interface of the A-alpha/B56-alpha/C heterotrimer, investigators identified RPT04402 as a potent activator. In vitro biochemical characterization demonstrated that RPT04402 selectively promoted B56-alpha heterotrimerization with both A-alpha P179R (Pro179 to Arg) and A-alpha S256F (Ser256 to Phe) mutant scaffolds. In vivo evaluation across multiple independent mutant cell line xenografts and patient-derived xenograft (PDX) mouse models established that monotherapy with RPT04402 drove significant tumor regressions and extended median overall survival without causing overt systemic toxicity or weight loss. Genetic knockouts confirmed mechanism-specificity, as the antitumor activity of RPT04402 was completely abrogated upon deletion of the B56-alpha subunit.

The authors conclude that RPT04402 represents a promising targeted strategy that directly corrects the driver mechanism of PPP2R1A-mutant high-grade uterine cancers. By successfully reassembling the tumor-suppressive PP2A A-alpha/B56-alpha/C heterotrimer in the presence of hotspot scaffolding mutations, this molecular glue platform offers a novel therapeutic approach for patients with refractory or recurrent gynecological malignancies.

Link to the article: https://www.science.org/doi/10.1126/scitranslmed.ady4852?referrer=https%3A%2F%2Fmedicalxpress.com%2F

References

Peris, I., Haanen, T. J., Day, A., Hu, J., Callahan, C., Hodges-Onishi, G., Zawacki, K. P., Tran, B., Harold, A., Dowdican, A., Nino, C. A., Huang, W., Leonard, D., Hinderman, M., Barrie, K., Raines, B., Sangodkar, J., Boock, S., Shankar, V., … Narla, G. (2026). Restoration of PP2A AαB56αC trimer formation by RPT04402 molecular glue in high-grade uterine cancer. Science Translational Medicine, 18(871), eady4852. https://doi.org/10.1126/scitranslmed.ady4852