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Tasquinimod Is an Allosteric Modulator of HDAC4 Survival Signaling within the Compromised Cancer Microenvironment

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Author

  • John T. Isaacs
  • Lizamma Antony
  • Susan L. Dalrymple
  • W. Nathaniel Brennen
  • Stephanie Gerber
  • Hans Hammers
  • Michel Wissing
  • Sushant Kachhap
  • Jun Luo
  • Li Xing
  • Per Bjork
  • Anders Olsson
  • Anders Bjork
  • Tomas Leanderson
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Summary, in English

Tasquinimod is an orally active antiangiogenic drug that is currently in phase III clinical trials for the treatment of castration-resistant prostate cancer. However, the target of this drug has remained unclear. In this study, we applied diverse strategies to identify the histone deacetylase HDAC4 as a target for the antiangiogenic activity of tasquinimod. Our comprehensive analysis revealed allosteric binding (Kd 10-30 nmol/L) to the regulatory Zn2+ binding domain of HDAC4 that locks the protein in a conformation preventing HDAC4/N-CoR/HDAC3 complex formation. This binding inhibited colocalization of N-CoR/HDAC3, thereby inhibiting deacetylation of histones and HDAC4 client transcription factors, such as HIF-1 alpha, which are bound at promoter/enhancers where epigenetic reprogramming is required for cancer cell survival and angiogenic response. Through this mechanism, tasquinimod is effective as a monotherapeutic agent against human prostate, breast, bladder, and colon tumor xenografts, where its efficacy could be further enhanced in combination with a targeted thapsigargin prodrug (G202) that selectively kills tumor endothelial cells. Together, our findings define a mechanism of action of tasquinimod and offer a perspective on how its clinical activity might be leveraged in combination with other drugs that target the tumor microenvironment. Cancer Res; 73(4); 1386-99. (C) 2012 AACR.

Department/s

  • Immunology

Publishing year

2013

Language

English

Pages

1386-1399

Publication/Series

Cancer Research

Volume

74

Issue

4

Document type

Journal article

Publisher

American Association for Cancer Research Inc.

Topic

  • Immunology in the medical area

Status

Published

Research group

  • Immunology

ISBN/ISSN/Other

  • ISSN: 1538-7445