Targeting the MLL complex in castration-resistant prostate cancer. Malik, R.; Khan, A. P.; Asangani, I. A.; Cieslik, M.; Prensner, J. R.; Wang, X.; Iyer, M. K.; Jiang, X.; Borkin, D.; Escara-Wilke, J.; Stender, R.; Wu, Y. M.; Niknafs, Y. S.; Jing, X.; Qiao, Y.; Palanisamy, N.; Kunju, L. P.; Krishnamurthy, P. M.; Yocum, A. K.; Mellacheruvu, D.; Nesvizhskii, A. I.; Cao, X.; Dhanasekaran, S. M.; Feng, F. Y.; Grembecka, J.; Cierpicki, T.; and Chinnaiyan, A. M. Nat Med, 2015.
doi  abstract   bibtex   
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.
@article{ malik2015,
  author = {Malik, R. and Khan, A. P. and Asangani, I. A. and Cieslik, M. and Prensner, J. R. and Wang, X. and Iyer, M. K. and Jiang, X. and Borkin, D. and 
Escara-Wilke, J. and Stender, R. and Wu, Y. M. and Niknafs, Y. S. and Jing, X. and Qiao, Y. and Palanisamy, N. and Kunju, L. P. and Krishnamurthy, P. M. and 
Yocum, A. K. and Mellacheruvu, D. and Nesvizhskii, A. I. and Cao, X. and Dhanasekaran, S. M. and Feng, F. Y. and Grembecka, J. and Cierpicki, T. and 
Chinnaiyan, A. M.},
  title = {Targeting the MLL complex in castration-resistant prostate cancer},
  journal = {Nat Med},
  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.},
  issn = {1078-8956},
  doi = {10.1038/nm.3830},
  year = {2015},
  type = {Journal Article}
}
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