Tasquinimod is an allosteric modulator of HDAC4 survival signaling within the compromised cancer microenvironment

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

Research output: Contribution to journalArticle

54 Scopus citations

Abstract

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-1a, 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.

Original languageEnglish (US)
Pages (from-to)1386-1399
Number of pages14
JournalCancer research
Volume73
Issue number4
DOIs
StatePublished - Jan 15 2013

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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    Isaacs, J. T., Antony, L., Dalrymple, S. L., Brennen, W. N., Gerber, S., Hammers, H., Wissing, M., Kachhap, S., Luo, J., Xing, L., Bjork, P., Olsson, A., Bjork, A., & Leanderson, T. (2013). Tasquinimod is an allosteric modulator of HDAC4 survival signaling within the compromised cancer microenvironment. Cancer research, 73(4), 1386-1399. https://doi.org/10.1158/0008-5472.CAN-12-2730