Targeting the MLL complex in castration-resistant prostate cancer.

Area of Science:

• Oncology
• Molecular Biology
• Cancer Therapeutics

Background:

• Castration-resistant prostate cancer (CRPC) is driven by resistance to androgen deprivation therapies and elevated androgen receptor (AR) activity.
• Therapeutic strategies targeting AR directly are established, but AR co-activators remain underexplored as potential targets.

Purpose of the Study:

• To investigate the role of the mixed-lineage leukemia (MLL) protein complex as a co-activator of AR signaling in prostate cancer.
• To evaluate the therapeutic potential of targeting the menin-MLL interaction in CRPC.

Main Methods:

• Investigated AR interaction with the MLL complex, specifically the menin-MLL subunit.
• Quantified menin expression in prostate cancer tissues and correlated it with patient survival.
• Utilized a small-molecule inhibitor of the menin-MLL interaction in preclinical models.

Main Results:

• The MLL complex directly interacts with AR via the menin-MLL subunit.
• Menin expression is significantly higher in CRPC compared to hormone-naive prostate cancer and benign tissues.
• Elevated menin expression correlates with poorer overall survival in prostate cancer patients.
• Inhibition of the menin-MLL interaction effectively blocked AR signaling and suppressed castration-resistant tumor growth in vivo.

Conclusions:

• The MLL complex functions as a critical co-activator of AR signaling.
• Targeting the menin-MLL interaction represents a promising therapeutic strategy for advanced prostate cancer.