Inhibition of MLL Blunts AR Signaling and Suppresses CRPC Growth

The standard-of-care treatment in prostate cancer comprises surgery, radiotherapy, and androgen deprivation therapies. However, no cure is currently available for hormone-refractory castration-resistant prostate cancer (CRPC), which is a primary cause of relapse and mortality. Malik and colleagues characterized a functional interaction between the mixed-lineage leukemia (MLL) histone methyltransferase complex and androgen receptor (AR) transcriptional activity, and showed that targeting the MLL complex inhibits CRPC growth. Immunopreciptation experiments demonstrated the interaction of AR with MLL complex proteins, including a direct interaction between the N-terminus of AR and the essential MLL cofactor menin. Depletion of MLL complex subunits resulted in a significant decrease in androgen-stimulated expression of AR target genes and diminished the growth of both prostate cancer cell lines and xenograft tumors. Genome-wide analyses showed that MLL and AR co-occupied many AR target genes and that MLL binding sites contain AR responsive elements, demonstrating the requirement of MLL as a coactivator of AR-driven transcription. In human prostate cancer samples, menin expression was elevated in metastatic CRPC compared with hormone-naïve prostate cancer and benign prostate tissue and was predictive of poor survival, supporting the idea that this MLL subunit promotes progression to CRPC. Pharmacologic inhibition of the menin–MLL interaction with the small-molecule inhibitors MI-136 or MI-503 resulted in attenuated expression of AR target genes, decreased cell viability, and increased apoptosis of prostate cancer cell lines, and suppressed the growth of castration-resistant xenograft tumors in vivo. Notably, treatment with these inhibitors disrupted the menin–MLL interaction, but not the menin–AR interaction, consistent with the requirement for MLL as a coactivator for AR signaling. In addition, combinatorial therapy with MI-503 and the FDA-approved anti-androgen MDV-3100 further reduced tumor growth in vivo. Overall, these findings highlight a functional relationship between AR and the MLL complex and provide a rationale for developing MLL-targeted therapies for the treatment of advanced CRPC.

Malik R, Khan AP, Asangani IA, Cieślik M, Prensner JR, Wang X, et al. Targeting the MLL complex in castration-resistant prostate cancer. Nat Med 2015;21:344–52.

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