MECOM Function Is Critical for AR-Driven Treatment-Resistant Prostate Cancer.

UNLABELLED: Reprogramming of the androgen receptor (AR) cistrome is associated with prostate cancer progression, and advanced castration-resistant prostate cancers (CRPC) tend to rely on reprogrammed/noncanonical AR signaling that remains active under treatment with AR signaling inhibitors (ARSI). In this study, we identified ecotropic viral integration site 1 (EVI1), an oncogenic nuclear transcription factor (TF) encoded by MECOM, as an AR-recruited coactivator of noncanonical signaling. In prostate cancer, MECOM was exclusively overexpressed in both CRPC and enzalutamide-resistant CRPC and interacted with AR in the nucleus. MECOM depletion in prostate cancer cells decreased proliferation, altered cell survival transcriptional programs, and reduced the number of super-enhancers (SE), leading to a dynamic change in the SE landscape and a decrease in the expression of SE-regulated oncogenic TFs, along with increased proapoptotic signatures. Notably, cells overexpressing MECOM and its protein, EVI1, were susceptible to PARP inhibitors (PARPi) regardless of their DNA damage response or homologous recombination repair (HRR) gene mutation status. These insights reveal the crucial role of EVI1 in regulating cell survival within the context of an AR-reprogrammed chromatin landscape. More importantly, the findings suggest that MECOM overexpression may be another biomarker that could significantly broaden the use of PARPis beyond those with HRR gene mutations.

SIGNIFICANCE: MECOM is a driver of androgen receptor inhibitor resistance in castrate-resistant prostate cancer that promotes susceptibility to PARP inhibition, positioning MECOM as a biomarker in patients without homologous recombination repair gene mutations.