Potential of β-catenin inhibitors as a novel therapeutic strategy for PIK3CA/CTNNB1 double-mutant endometrial cancer

Abstract

Endometrial cancer (EC) is one of the most prevalent gynecological malignancies. EC is characterized by limited therapeutic options and a substantial unmet medical need, particularly in advanced or metastatic stages. Although a high prevalence of concurrent PIK3CA and CTNNB1 mutations has been reported in patients with EC, the functional interplay between the phosphatidylinositol 3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) and Wnt/β-catenin signaling pathways remains unclear. In this study, we investigated the therapeutic potential of targeting these pathways in PIK3CA and CTNNB1 double-mutant ECs. In vitro growth assays across 11 EC cell lines evaluated the Wnt/β-catenin inhibitor ICG-001, the AKT inhibitor ipatasertib, and the mTOR inhibitor rapamycin. Notably, ICG-001, but not the PI3K/AKT/mTOR pathway inhibitors, exhibited potent antiproliferative activity specifically in CTNNB1 / PIK3CA double-mutant cells. Transcriptomic profiling revealed that a series of canonical β-catenin target genes were downregulated, while signature genes related to proteotoxic stress and proteostasis disruption were significantly enriched in the ICG-001-treated CTNNB1 / PIK3CA double-mutant cells. Mechanistically, ICG-001 induced de novo protein synthesis, autophagosome formation (LC3B-II accumulation), endoplasmic reticulum expansion, and the accumulation of ubiquitinated proteins, indicating severe proteostasis collapse. Furthermore, daily administration of ICG-001 demonstrated robust antitumor efficacy in CTNNB1 / PIK3CA double-mutant EC xenograft models, accompanied by marked ubiquitin accumulation within xenograft tissues. Collectively, these preclinical findings highlight the vulnerability of PIK3CA / CTNNB1 double-mutant ECs to β-catenin inhibition and establish β-catenin/CBP inhibitors as a promising targeted therapeutic strategy for this specific genetic subset.