Abstract
Abstract Resistance to androgen deprivation therapies and increased androgen receptor (AR) activity are major drivers of castrate resistant prostate cancer (CRPC), an advanced and frequently lethal form of this disease. Substantial prior work has focused on targeting AR directly; however, the identification and therapeutic targeting of co-activators of AR signaling remains an underexplored area of potential clinical significance. Here we demonstrate that the MLL complex acts as a co-activator of AR signaling. AR directly interacts with the sub-unit menin to recruit MLL and its complex to AR target genes. Inhibition of the menin-MLL interaction can block AR signaling and inhibit the formation of castration resistant tumors in vivo. Furthermore, we find that menin is up-regulated in localized and metastatic prostate cancer and high menin expression correlates with poor overall survival. Taken together our study identifies a novel co-activator complex of AR that can be targeted in CRPCs. Citation Format: Rohit Malik, Amjad P. Khan, John R. Prensner, Matthew K. Iyer, Dmitry Borkin, Xiaoju Wang, Xia Jiang, Shruthi Subramaniam, Yang Shi, Rachell Stender, Yi-Mi Wu, Xuhong Cao, Jolanta Grembecka, Tomasz Cierpicki, Arul Chinnaiyan. Targeting novel co-activators of androgen receptor in castration resistant prostate cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1398. doi:10.1158/1538-7445.AM2014-1398
Published Version
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