Restoration of PP2A AαB56αC trimer formation by RPT04402 molecular glue in high-grade uterine cancer
Menée à l'aide de lignées cellulaires, de modèles murins et de xénogreffes issues de patientes atteintes d'une tumeur utérine de haut grade, cette étude identifie une série de "colles moléculaires" (notamment la molécule RPT04402) qui restaurent la formation du trimère PP2A lors de la présence de mutations P179R ou S256F, puis met en évidence l'intérêt de cette approche thérapeutique pour réduire la progression tumorale et améliorer la survie
The incidence and mortality of high-grade endometrial cancers are increasing, and heterozygous hotspot mutations in PPP2R1A are drivers of the most aggressive forms of uterine cancer. PPP2R1A encodes the Aα scaffolding subunit of the heterotrimeric phosphatase PP2A. These recurrent mutations, specifically at the Pro179 and Ser256 residues, disrupt the binding of tumor-suppressive substrate-directing B56 and B55 subunits to the PP2A scaffolding subunit while maintaining binding to other regulatory subunits. Here, we identified a series of molecular glues that correct PP2A trimer formation in the context of the P179R (Pro179→Arg) and S256F (Ser256→Phe) mutants. A small-molecule library was designed to fit into the pocket at the binding interface of the Aα/B56α/C heterotrimer. The lead molecule, RPT04402, promoted B56α heterotrimerization to the AαP179R and AαS256F mutant scaffolds. In mice, RPT04402 treatment drove tumor regressions and extended median survival in multiple independent mutant cell lines and patient-derived xenografts, proving a robust single-agent activity. This activity was abrogated upon knockout of B56α. Combined, these data demonstrate that PP2A molecular glues are a promising first-in-class therapy that might benefit patients with PPP2R1A mutant uterine cancer by targeting a driver of this aggressive disease. The PP2A molecular glue RPT04402 restores mutant Aα PP2A heterotrimer formation in highly aggressive uterine cancer.
Science Translational Medicine , résumé, 2026