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Updated: Apr 15, 2026
A Bioluminescent and Fluorescent Orthotopic Syngeneic Murine Model of Androgen-dependent and Castration-resistant Prostate Cancer
Published on: March 6, 2018
Targeting the MLL complex in castration-resistant prostate cancer
Rohit Malik1, Amjad P Khan1, Irfan A Asangani1
11] Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, Michigan, USA. [2] Department of Pathology, University of Michigan, Ann Arbor, Michigan, USA.
Abstract:
Resistance to androgen deprivation therapies and increased androgen receptor (AR) activity are major drivers of castration-resistant prostate cancer (CRPC). Although prior work has focused on targeting AR directly, co-activators of AR signaling, which may represent new therapeutic targets, are relatively underexplored. Here we demonstrate that the mixed-lineage leukemia protein (MLL) complex, a well-known driver of MLL fusion-positive leukemia, acts as a co-activator of AR signaling. AR directly interacts with the MLL complex via the menin-MLL subunit. Menin expression is higher in CRPC than in both hormone-naive prostate cancer and benign prostate tissue, and high menin expression correlates with poor overall survival of individuals diagnosed with prostate cancer. Treatment with a small-molecule inhibitor of menin-MLL interaction blocks AR signaling and inhibits the growth of castration-resistant tumors in vivo in mice. Taken together, this work identifies the MLL complex as a crucial co-activator of AR and a potential therapeutic target in advanced prostate cancer.
Insights
The mixed-lineage leukemia (MLL) protein complex co-activates androgen receptor (AR) signaling in castration-resistant prostate cancer (CRPC). Inhibiting the menin-MLL interaction offers a potential therapeutic strategy for advanced 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.
