Abstract 3146: Targeting KMT2D enhances sensitivity to AKT inhibition in treatment resistant prostate cancer

Abstract Prostate cancer (PCa) is the leading cause of cancer-related deaths in men, with over 299,000 new cases expected in the U.S. in 2024 alone. A loss-of-function mutation in the PTEN gene activates the PI3K-Akt-mTOR pathway, driving increased cell proliferation and metastasis. Prior studies from our group and others have shown that the AKT signaling pathway remains an attractive target in advanced prostate cancers and other solid tumors. In breast cancer, inhibition of the PI3K pathway has been shown to activate KMT2D, a histone lysine dimethyltransferase. Activation of KMT2D enhanced hormone-regulated gene expression and, in turn, enhanced the response to hormone-targeted therapies. We modified treatment-resistant human PCa cell lines (C4-2B ER, LREX) to suppress AKT isoforms using shRNAs. Using these models, we observed increased KMT2D expression and activity, as indicated by increased H3K4 dimethylation, with suppression of AKT2 and AKT3, but not AKT1, isoforms. In addition, we observed increased androgen receptor (AR) expression. Conversely, knocking down KMT2D in the C42B cell line resulted in a significant decrease in proliferation and increased sensitivity to the Akt inhibitor (Ipatasertib). Although preliminary, these findings suggest that KMT2D may be involved in cross-talk with the PI3K-AKT signaling pathway with implications for AR signaling. Citation Format: Abbas Jawadwala, Remi M. Adelaiye-Ogala, Surendra Gulla, Tej K. Sharma, Ephraim Jeremiah Gardner, Maddie Aust. Targeting KMT2D enhances sensitivity to AKT inhibition in treatment resistant prostate 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 3146.