Abstract 1324: MECOM a novel player in AR-driven treatment resistant castration-resistant prostate cancer

The androgen receptor (AR) remains a pivotal target in castration-resistant prostate cancer (CRPC), as its continued activity presents a therapeutic vulnerability. Reprogramming of the AR cistrome, shifting from a canonical (typical or standard) to a non-canonical (atypical or non-standard) form, is associated with disease progression. While canonical AR signatures are prevalent in benign and localized prostate cancer, advanced CRPC exhibits a predominance of non-canonical AR elements. This non-canonical AR cistrome is linked to enzalutamide resistance, a standard AR-targeted therapy in the clinic. In preclinical prostate cancer models, non-canonical AR signatures correlate with enzalutamide resistance, and bulk RNA sequencing and AR-ChIP-seq data suggest an association with the EVI1-target gene set. EVI1, a zinc-finger transcription factor and product of the MECOM locus, is associated with poor prognosis and acts as a co-activator in cancer cell survival. Yet, its role in AR therapy resistance remains unclear. Functional assays demonstrated that MECOM expression, confined to CRPC and enzalutamide-resistant models, interacts with AR and influences cell proliferation. MECOM knockdown in CRPC cells inhibited proliferation in 2D and 3D cell cultures and significantly affected noncanonical AR signature profiles. This suggests a potential re-sensitization to AR inhibitors, a finding that could significantly impact the treatment of CRPC. Poly-ADP ribose polymerase inhibitors (PARPi), particularly Talazoparib, effectively reduced tumor growth in vivo and MECOM protein expression in CRPC cells, organoids derived from PDXs, and tumors. Our findings indicate that MECOM is a key driver of non-canonical AR signaling in CRPC. We propose that patients with MECOM expression may benefit from PARPi therapy, regardless of DNA Damage Repair (DDR) or homologous DNA Repair (HDR) gene mutation status. Citation Format: Surendra Gulla, Tej K. Sharma, Ephraim Gardner, Shreya Shyam Sundar, Brian Capaldo, Jonathan E. Bard, Tobi Ogunbowale, Abbas Jawadala, Min Ma, Roberto Pili, Jun Qu, David J. VanderWeele, Remi Adelaiye-Ogala. MECOM a novel player in AR-driven treatment resistant castration-resistant prostate cancer [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 1324.