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

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.

Antony, Lizamma (author)
Dalrymple, Susan L. (author)
Brennen, W. Nathaniel (author)
Gerber, Stephanie (author)
Hammers, Hans (author)
Wissing, Michel (author)
Kachhap, Sushant (author)
Luo, Jun (author)
Xing, Li (author)
Bjork, Per (author)
Olsson, Anders (author)
Bjork, Anders (author)
Leanderson, TomasLund University,Lunds universitet,Immunologi,Forskargrupper vid Lunds universitet,Immunology,Lund University Research Groups(Swepub:lu)immu-tle (author)
ImmunologiForskargrupper vid Lunds universitet (creator_code:org_t)

By the author/editor: Isaacs, John T.; Antony, Lizamma; Dalrymple, Susan ...; Brennen, W. Nath ...; Gerber, Stephani ...; Hammers, Hans; show more...; Wissing, Michel; Kachhap, Sushant; Luo, Jun; Xing, Li; Bjork, Per; Olsson, Anders; Bjork, Anders; Leanderson, Toma ...; show less...

About the subject

MEDICAL AND HEALTH SCIENCES: MEDICAL AND HEAL ...; and Basic Medicine; and Immunology in th ...

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