Abstract 6948: A PP2A molecular glue restores heterotrimer formation for the treatment of high-grade uterine cancers

Abstract Uterine cancer incidence and mortality have been increasing, particularly in the aggressive high-grade subtypes, including uterine serous carcinomas (USC) and uterine carcinosarcomas (UCS). For the high-grade subtypes, surgery remains the mainstay of treatment, and while the approval of the combination of Pembrolizumab and Lenvatinib is a promising treatment strategy, there is only a 50% response rate in women with recurrent disease, highlighting the need for additional therapeutic options. Molecularly, these tumors harbor few mutations and are hallmarked by copy number alterations. However, almost every USC tumor harbors a TP53 mutation, and 30-40% of patients also harbor a co-occurrent mutation to PPP2R1A. Heterozygous hotspot mutations in PPP2R1A are drivers of the most aggressive forms of uterine cancer. PPP2R1A encodes for the Aα scaffolding subunit of the heterotrimeric phosphatase PP2A. The PP2A heterotrimeric complex is comprised of a catalytic (C) subunit, a scaffolding (A) subunit, and a substrate-directing regulatory (B) subunit. The binding of different classes of regulatory B subunits directs PP2A’s serine/threonine phosphatase activity. We, and other groups, have shown that these hotspot mutations result in a biased pool of heterotrimers, where the formation of tumor-suppressive holoenzymes is abrogated while leaving tumor-promoting heterotrimers intact. Here, we identify small molecular glues that could therapeutically correct trimer formation to the mutant scaffold. A small molecule library was designed to fit into the pocket at the interface of Aα/B56α/Cα. The molecule RPT04402 promoted B56α heterotrimerization to the AαP179R and AαS256F mutant scaffolds. In mice, RPT04402 treatment presented tumor regressions and median survival extensions in multiple independent cell-derived and patient-derived xenografts. Importantly, this activity was abrogated upon knockout of B56α. This molecule has undergone preclinical toxicology studies and is well tolerated in multiple species. Combined, these data demonstrate that PP2A molecular glues are a promising novel therapy for PPP2R1A mutant uterine cancer patients and represent the first small molecule approach targeting a driver of this aggressive disease. Citation Format: Irene Peris, Derek Taylor, George Trainor, Analisa V. DiFeo, Caitlin O'Connor, Goutham Narla. A PP2A molecular glue restores heterotrimer formation for the treatment of high-grade uterine cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 6948.