Targeting the MLL complex in castration-resistant prostate cancer

Rohit Malik; Amjad P Khan; Irfan A Asangani; Marcin Cieślik; John R Prensner; Xiaoju Wang; Matthew K Iyer; Xia Jiang; Dmitry Borkin; June Escara-Wilke; Rachell Stender; Yi-Mi Wu; Yashar S Niknafs; Xiaojun Jing; Yuanyuan Qiao; Nallasivam Palanisamy; Lakshmi P Kunju; Pranathi M Krishnamurthy; Anastasia K Yocum; Dattatreya Mellacheruvu; Alexey I Nesvizhskii; Xuhong Cao; Saravana M Dhanasekaran; Felix Y Feng; Jolanta Grembecka; Tomasz Cierpicki; Arul M Chinnaiyan

doi:10.1038/nm.3830

Targeting the MLL complex in castration-resistant prostate cancer

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

Authors

Rohit Malik¹, Amjad P Khan¹, Irfan A Asangani¹, Marcin Cieślik¹, John R Prensner¹, Xiaoju Wang¹, Matthew K Iyer¹, Xia Jiang¹, Dmitry Borkin², June Escara-Wilke¹, Rachell Stender¹, Yi-Mi Wu¹, Yashar S Niknafs³, Xiaojun Jing¹, Yuanyuan Qiao¹, Nallasivam Palanisamy⁴, Lakshmi P Kunju⁵, Pranathi M Krishnamurthy³, Anastasia K Yocum³, Dattatreya Mellacheruvu⁶, Alexey I Nesvizhskii⁷, Xuhong Cao⁸, Saravana M Dhanasekaran¹, Felix Y Feng⁹, Jolanta Grembecka², Tomasz Cierpicki², Arul M Chinnaiyan¹⁰

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
PMCID: PMC4390530
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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Animals
Cell Line, Tumor
Cell Nucleus / metabolism
Cell Proliferation
Drug Resistance, Neoplasm*
Histone-Lysine N-Methyltransferase / metabolism
Humans
Male
Mice
Mice, SCID
Myeloid-Lymphoid Leukemia Protein / metabolism*
Neoplasm Metastasis
Neoplasm Transplantation
Prostatic Neoplasms
Prostatic Neoplasms, Castration-Resistant / drug therapy
Prostatic Neoplasms, Castration-Resistant / metabolism*
Proto-Oncogene Proteins / metabolism*
Receptors, Androgen / metabolism*
Signal Transduction
Treatment Outcome

Substances

AR protein, human
KMT2A protein, human
MEN1 protein, human
Men1 protein, mouse
Proto-Oncogene Proteins
Receptors, Androgen
Myeloid-Lymphoid Leukemia Protein
Histone-Lysine N-Methyltransferase
Kmt2a protein, mouse

Associated data

GEO/GSE60842

Abstract

Publication types

MeSH terms

Substances

Associated data

Grants and funding