Abstract 3913: Inavolisib demonstrates anti-tumorigenic effects in pre-clinical models of serous endometrial cancer.

Abstract Objectives: Inavolisib is an oral selective PI3K inhibitor that has shown promising anti-tumorigenic activity in multiple pre-clinical models of cancer as well as breast cancer clinical trials, via promoting the degradation of mutated p110α, the catalytic subunit encoded by PIK3CA. The phosphatidylinositol 3-kinase (PI3K) signaling cascade is critically implicated in the tumorigenesis and progression of uterine serous carcinoma (USC), one of the most aggressive subtypes of endometrial cancer (EC). Given the urgent need to develop more effective treatment interventions for this highly lethal subtype of EC and that PI3Ka alterations are common in USC, we aimed to investigate the anti-tumorigenic and anti-invasive activities of inavolisib in serous EC cell lines. Methods: The human serous EC cell lines, ARK1 and ARK2, were used in this study and treated with inavolisib (obtained from Genentech). Cell proliferation was evaluated by MTT assay. Cell cycle progression was examined by Cellometer. Cellular stress was evaluated by DCFH-DA assay and change in mitochondrial membrane potential was measured by JC-1 assay. Apoptosis was evaluated using a cleaved caspase-3 assay. Cell adhesion was evaluated using a laminin-1 assay, and cell migration was assessed by wound healing assay. Western immunoblotting was used to measure downstream protein expression related to cell cycle progression, cellular stress, and apoptosis. Results: After 72 hours of treatment with inavolisib, the proliferation of ARK1 and ARK2 cells was inhibited in a dose-dependent manner (IC50: ARK1 674 nM, ARK2 2969 nM). Treatment of both cell lines with inavolisib significantly arrested the cell cycle at the G1 phase, increased intracellular reactive oxygen species levels, and decreased mitochondrial membrane potential compared with untreated cells (p<0.05). Inavolisib also significantly increased the activity of cleaved caspase-3 and reduced the expression of BcL-2 and MCL-1 in both cell lines. Moreover, inavolisib effectively decreased cell adhesion and migration at doses of 100 and 250 nM in the ARK1 and ARK2 cells (p<0.05). Western immunoblotting results demonstrated that treatment with inavolisib downregulated the expression of downstream targets of the PIK3CA/mTOR pathway (phosphorylated [p]-AKT, p-S6) and the cell cycle proteins CDK4 and cyclin D1 and upregulated the expression of the pro-apoptotic Bax and PDI proteins in both cells. Conclusions: Inavolisib exhibits potent anti-tumorigenic and anti-invasive effects in serous EC cell lines, suggesting that this novel agent is a promising therapeutic option worthy of further exploration in the treatment of aggressive serous ECs. Citation Format: Miller Singleton, Haomeng Zhang, Alexandra Diggs, Braxton Burnett, Kristen N. Taylor, Chunxiao Zhou, Victoria Lin Bae-Jump. Inavolisib demonstrates anti-tumorigenic effects in pre-clinical models of serous endometrial cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 3913.