Targeting the MLL complex in castration-resistant prostate cancer

  • Nat Med. 2015 Apr;21(4):344-52. doi: 10.1038/nm.3830.
Rohit Malik  1 ,  Amjad P Khan  1 ,  Irfan A Asangani  1 ,  Marcin Cieślik  1 ,  John R Prensner  1 ,  Xiaoju Wang  1 ,  Matthew K Iyer  1 ,  Xia Jiang  1 ,  Dmitry Borkin  2 ,  June Escara-Wilke  1 ,  Rachell Stender  1 ,  Yi-Mi Wu  1 ,  Yashar S Niknafs  3 ,  Xiaojun Jing  1 ,  Yuanyuan Qiao  1 ,  Nallasivam Palanisamy  4 ,  Lakshmi P Kunju  5 ,  Pranathi M Krishnamurthy  3 ,  Anastasia K Yocum  3 ,  Dattatreya Mellacheruvu  6 ,  Alexey I Nesvizhskii  7 ,  Xuhong Cao  8 ,  Saravana M Dhanasekaran  1 ,  Felix Y Feng  9 ,  Jolanta Grembecka  2 ,  Tomasz Cierpicki  2 ,  Arul M Chinnaiyan  10
Affiliations
  • 1. 1] Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, Michigan, USA. [2] Department of Pathology, University of Michigan, Ann Arbor, Michigan, USA.
  • 2. Department of Pathology, University of Michigan, Ann Arbor, Michigan, USA.
  • 3. Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, Michigan, USA.
  • 4. 1] Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, Michigan, USA. [2] Department of Pathology, University of Michigan, Ann Arbor, Michigan, USA. [3] Department of Urology, Henry Ford Health System, Detroit, Michigan, USA.
  • 5. 1] Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, Michigan, USA. [2] Department of Pathology, University of Michigan, Ann Arbor, Michigan, USA. [3] Comprehensive Cancer Center, University of Michigan, Ann Arbor, Michigan, USA.
  • 6. 1] Department of Pathology, University of Michigan, Ann Arbor, Michigan, USA. [2] Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, Michigan, USA.
  • 7. 1] Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, Michigan, USA. [2] Department of Pathology, University of Michigan, Ann Arbor, Michigan, USA. [3] Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, Michigan, USA.
  • 8. 1] Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, Michigan, USA. [2] Howard Hughes Medical Institute, University of Michigan, Ann Arbor, Michigan, USA.
  • 9. 1] Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, Michigan, USA. [2] Radiation Oncology, University of Michigan, Ann Arbor, Michigan, USA. [3] Department of Urology, University of Michigan, Ann Arbor, Michigan, USA.
  • 10. 1] Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, Michigan, USA. [2] Department of Pathology, University of Michigan, Ann Arbor, Michigan, USA. [3] Comprehensive Cancer Center, University of Michigan, Ann Arbor, Michigan, USA. [4] Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, Michigan, USA. [5] Howard Hughes Medical Institute, University of Michigan, Ann Arbor, Michigan, USA. [6] Department of Urology, University of Michigan, Ann Arbor, Michigan, USA.
PMID: 25822367 DOI: 10.1038/nm.3830
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.

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