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Targeting the MLL complex in castration-resistant prostate cancer

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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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Figure 1: Androgen receptor interacts with MLL-complex proteins.
Figure 2: MLL-complex proteins are important for AR signaling and cell growth.
Figure 3: AR and ASH2L are recruited to the same genomic loci upon androgen stimulation.
Figure 4: AR directly interacts with menin.
Figure 5: Menin is upregulated in both localized and metastatic CRPC.
Figure 6: A menin–MLL small molecule inhibitor impairs prostate cancer growth in mice.

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Acknowledgements

We thank A. Poliakov, J. Siddiqui and S. Shukla for helpful discussions; B. Malik, S. Subramanian, K. Wilder-Romans, S. Yazdani and V.L. Dommeti for technical assistance; K. Giles and C. Betts for critically looking over the manuscript and the submission of documents; the University of Michigan Viral Vector Core for generating the lentiviral constructs and Microscopy and Image-analysis Laboratory (MIL) for help with immunofluorescence microscopy. We thank C. Sawyers (Memorial Sloan-Kettering Cancer Center) for the LNCaP-AR cell line. This work was supported in part by the US National Institutes of Health (NIH) Prostate Specialized Program of Research Excellence grant (P50CA186786) and the Early Detection Research Network grant (UO1 CA111275) to A.M.C. A.M.C. is supported by the Prostate Cancer Foundation and the Howard Hughes Medical Institute. A.M.C. is an American Cancer Society Research Professor and a Taubman Scholar of the University of Michigan. J.G. is supported by the NIH R01 grant (1R01CA160467) and The Leukemia & Lymphoma Society Translational Research Program grant (6116-12). T.C. is supported by the American Cancer Society Research Scholar grant (RSG-11-082-01-DMC). A.N. is supported by US NIH grant R01-GM-094231. R.M is supported by a Department of Defense post-doctoral award (W81XWH-13-1-0284). R.M., I.A.A. and M.C. are supported by a Prostate Cancer Foundation Young Investigator award.

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R.M., A.P.K. and A.M.C. conceived and designed the research. R.M. performed most experiments with the help of A.P.K., I.A.A., J.R.P., X. Jiang, X.W., Y.Q. and P.M.K. R.M. and X.W. carried out in vitro interaction studies. X. Jing performed microarray and M.C. analyzed the data. M.K.I. analyzed ChIP-seq data. M.K.I. and Y.S.N. performed gene expression analysis. J.E.-W., R.S. and F.Y.F. performed mouse xenograft studies. Y.-M.W. generated ChIP-seq libraries and X.C. performed the sequencing. N.P. and L.P.K. performed IHC. A.I.N., A.K.Y. and D.M. assisted with data analysis. D.B., J.G. and T.C. provided inhibitors. R.M. and A.M.C. wrote the manuscript with help from S.M.D., I.A.A. and A.P.K. All authors discussed the results and commented on the manuscript.

Corresponding author

Correspondence to Arul M Chinnaiyan.

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Competing interests

A provisional patent application (US application number PCT/US14/22750) has been filed by The University of Michigan on the use of menin inhibitors described in this study. J.G., D.B. and T.C. are named as co-inventors.

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Supplementary Text and Figures

Supplementary Figures 1–13 (PDF 4220 kb)

Supplementary Table 1

Genes closest to AR induced ASH2L peaks (XLS 36 kb)

Supplementary Table 2

List of Antibodies used (XLS 25 kb)

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Malik, R., Khan, A., Asangani, I. et al. Targeting the MLL complex in castration-resistant prostate cancer. Nat Med 21, 344–352 (2015). https://doi.org/10.1038/nm.3830

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