MECOM: A novel player in AR-driven Treatment Resistant Castration-Resistant Prostate Cancer

Reprogramming of the androgen receptor (AR) cistrome is associated with disease progression, and advanced castrate-resistant prostate cancers (CRPC) tend to rely on a reprogrammed/non-canonical AR signaling that is addictive to AR signaling inhibitor (ARSI) resistance. We identified EVI1, an oncogenic nuclear transcription factor, EVI1 coded by MECOM, as a novel AR-recruited co-activator for non-canonical signaling. MECOM is exclusively overexpressed CRPC and enzalutamide-resistant CRPC and interacts with AR in the nucleus. MECOM knockdown cells exhibited decreased proliferation and critical cell survival transcriptional programs, suppressed super-enhancer (SE) activity, and affected non-canonical AR signature profiles. Intriguingly, MECOM overexpression is vulnerable to PARP inhibitors regardless of DDR or HRR gene mutation status. These insights uncover the mechanistic role of MECOM in AR reprogrammed cistrome and its vulnerability. More importantly, this study suggests that MECOM overexpression may be another biomarker that could significantly broaden the use of PARP inhibitors beyond those with HRR gene mutations. Overall design: RNA-Seq Profiling of wild type LREX, C42B-ER, CWR-R1 cells and their knockdown derivatives(ShMECOM). CHIP-Seq Profiling on AR and H3K27ac pull downs on various cell lines LREX, C4-2BER and CWR-R1 wild type and ShMECOM knock down conditions.