Abstract 563: AR-dependent castration-resistant prostate cancer relies on histone methyltransferase KMT2D for cell growth

The KMT2D histone H3 lysine 4 (H3K4) methyltransferase plays critical roles in enhancer-regulated gene activation. It is a large multi-domain protein with its C-terminal SET domain being responsible for this activity. High KMT2D expression is associated with reduced patient survival in prostate cancer. Cancer Dependency Map data show a correlation between KMT2D gene dependency and FOXA1 expression in prostate cancer cell lines. FOXA1 is a major regulator of Androgen Receptor (AR) transcription and recent findings showed that KMT2D establishes the chromatin competency to recruit AR and for FOXA1 to activate AR-dependent transcription. Since FOXA1 is predicted to be poorly tractable, we aimed to target the more tractable KMT2D in FOXA1-overexpressing AR-dependent castration-resistant prostate cancer (CRPC). CRPC cell lines with high FOXA1 (FOXA1high) and high AR (ARhigh) and/or AR constitutively active splice variants, such as AR-V7 (AR-V7+) were found to express high levels of KMT2D. KMT2D knockout (KO) reduced cell growth in these cells and in isogenic AR-V7+ 22Rv1 cells lacking full length AR. Additionally, KMT2D KO modulated AR target genes as demonstrated by reduced PSA mRNA and increased mRNA for IGFBP3 and EFNB2. Inactivating SET domain mutations demonstrated that these effects were mediated by KMT2D’s catalytic function thus supporting SET-domain inhibition as the desired target modality. This study highlights the potential of KMT2D as a therapeutic target for AR-dependent CRPC patients with constitutively active AR splice variants who have high unmet medical need due to AR variants being undruggable with currently available therapeutic agents. Citation Format: Angela Bononi, Paul Redford, Weichao Zhang, Gabriella Cifelli, Sungtae Kim, Ian Gao, Kelly Werth, Peter Carman, Gilberto Valdes Garcia, Zane Taylor, Rachel Totoritis, Jess Schneck, Paul Bamborough, Markus Queisser, Georgia Maundrill, Dean Thomas, Hoang Tran, Sarvesh Varma, Biju Mangatt, Michael McCabe, Benjamin Schwartz, Kelly Choi. AR-dependent castration-resistant prostate cancer relies on histone methyltransferase KMT2D for cell growth [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 563.