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- Title
Targeting the MLL complex in castration-resistant prostate cancer.
- Authors
Malik, Rohit; Khan, Amjad P; Asangani, Irfan A; Cieślik, Marcin; Prensner, John R; Wang, Xiaoju; Iyer, Matthew K; Jiang, Xia; Borkin, Dmitry; Escara-Wilke, June; Stender, Rachell; Wu, Yi-Mi; Niknafs, Yashar S; Jing, Xiaojun; Qiao, Yuanyuan; Palanisamy, Nallasivam; Kunju, Lakshmi P; Krishnamurthy, Pranathi M; Yocum, Anastasia K; Mellacheruvu, Dattatreya
- 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.
- Subjects
PROSTATE cancer treatment; ANDROGEN receptors; CASTRATION; ANDROGENS; DRUG resistance in cancer cells; LEUKEMIA; MENIN
- Publication
Nature Medicine, 2015, Vol 21, Issue 4, p344
- ISSN
1078-8956
- Publication type
Article
- DOI
10.1038/nm.3830