Menin-driven mTOR signaling sustains taxane resistance in CRPC and reveals a targetable vulnerability for combination therapy

Prostate cancer (PC) progression is predominantly driven by androgen signaling, making androgen deprivation therapy (ADT) the standard treatment. However, the transition to castration-resistant prostate cancer (CRPC) significantly reduces ADT efficacy. While taxanes such as docetaxel (Dtx) and cabazitaxel (Cbz) are widely employed, therapeutic resistance remains a major clinical obstacle. To address this, we established docetaxel-resistant CRPC models and performed an epigenetic drug screen, identifying MLL-Menin and MLL-WDR5 inhibitors as potent agents capable of restoring taxane sensitivity through G₂/M arrest and apoptosis induction. Functional depletion of Menin (MEN1) revealed its critical role in sustaining chemoresistance, selectively impairing proliferation in resistant cells, and preventing resistance emergence in parental lines.Integrative transcriptomic (RNA-seq) and epigenomic (CUT&RUN-seq) analyses suggested that Menin may play a regulatory role in mTOR signaling and E2F target pathways. Menin binding to the promoters of mTOR and Cyclin D1 was confirmed, and rescue experiments further validated its regulatory role. Analysis of TCGA datasets demonstrated co-expression of MEN1 and mTOR in advanced metastatic PC, supporting clinical relevance. Moreover, combination treatment with the mTOR inhibitor Torin-1 and docetaxel synergistically enhanced therapeutic response in Menin-depleted resistant cells. MEN1 knockdown also abrogated tumor growth in vivo.These findings identify Menin as one of the key mediator of taxane resistance in CRPC through the regulation of mTOR. Targeting Menin, alone or in combination with mTOR inhibition, represents a promising strategy to overcome resistance and improve therapeutic outcomes in taxane-refractory PC.