靶向KMT2D增强治疗耐药性前列腺癌对AKT抑制的敏感性

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.