Abstract IA012: The role of the serine/threonine phosphatase PP2A in endometrial cancer development and progression: lessons learned from mutations and small molecules

Abstract Uterine cancer is the most common gynecologic malignancy in the United States with approximately 60, 000 new diagnoses each year. While many cases of uterine endometrial carcinoma (EMCA) have favorable outcomes with recurrence-free long-term survival, outcomes for the high-grade, treatment-refractory histological subtypes, including uterine serous carcinoma (USC) and uterine carcinosarcoma (UCS), remain an important clinical problem. Uterine serous carcinomas and uterine carcinosarcomas tumors are the most aggressive subtypes of uterine cancer, displaying a high propensity to invade the peritoneal cavity and to metastasize to distant sites. Accordingly, 50-70% of high-grade tumors exhibit extrauterine spread at time of initial surgery and have limited treatment options. The inherent aggressiveness of these tumors suggests that they are intrinsically equipped to disseminate and propagate tumors at secondary sites. The molecular drivers of this phenotype, however, have yet to be completely characterized. A lack of established and validated molecular drivers of the high-grade subtypes, especially those that are responsible for the high rate of metastasis, has limited the use of targeted treatment strategies. However, we and other groups have shown that PPP2R1A, the scaffolding subunit of the tumor suppressor protein phosphatase 2A, is mutated in up to 40% of USC patients, and these recurrent mutations are found at both the primary and metastatic sites. These mutations are heterozygous, and two specific mutations: P179R and S256F, occur exclusively within these high-grade subtypes of uterine cancer (i. e. , are not found in any other cancer type). PP2A, is a family of serine/threonine phosphatases, where the active heterotrimeric form of the enzyme is comprised of a catalytic (C) subunit, a scaffolding (A) subunit, and a substrate directing regulatory (B) subunit. In aggregate, PP2A is considered a tumor suppressor protein, but certain heterotrimers have tumor promoting roles. Here we present data related to the molecular and biological basis through which these recurrent pathogenic mutations drive endometrial cancer development and progression using disease relevant cellular and in vivo model systems. Additionally, building from previously published work from our group, we have developed a novel series of small molecule molecular glues (PMGs) that specifically correct the mutant heterotrimer driving tumor regressions in both cellular and patient derived xenograft models of high-grade endometrial cancer. Collectively, this data suggests that recurrent pathogenic mutations in the PPP2R1A gene drive endometrial cancer pathogenesis and these mutations can be therapeutically targeted using a series of pharmaceutically tractable small molecules. Citation Format: Goutham Narla. The role of the serine/threonine phosphatase PP2A in endometrial cancer development and progression: lessons learned from mutations and small molecules abstract. In: Proceedings of the AACR Special Conference on Endometrial Cancer: Transforming Care through Science; 2023 Nov 16-18; Boston, Massachusetts. Philadelphia (PA): AACR; Clin Cancer Res 2024;30 (5Suppl): Abstract nr IA012.