Publication in Nature Medicine

Nat Med. 2015 Apr;21(4):344-52. doi: 10.1038/nm.3830. Epub 2015 Mar 30.

Targeting the MLL complex in castration-resistant prostate cancer.

Malik R1, Khan AP1, Asangani IA1, Cieślik M1, Prensner JR1, Wang X1, Iyer MK1, Jiang X1, Borkin D2, Escara-Wilke J1, Stender R1, Wu YM1, Niknafs YS3, Jing X1, Qiao Y1, Palanisamy N4, Kunju LP5, Krishnamurthy PM3, Yocum AK3, Mellacheruvu D6, Nesvizhskii AI7, Cao X8, Dhanasekaran SM1, Feng FY9, Grembecka J2, Cierpicki T2, Chinnaiyan AM10.

Author information

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. 

PMID:

 

25822367

 

[PubMed - in process]