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

• Published in: Cancer research (Chicago, Ill.) Vol. 73; no. 4; pp. 1386 - 1399
• Main Authors: ISAACS, John T, ANTONY, Lizamma, BJÖRK, Per, OLSSON, Anders, BJÖRK, Anders, LEANDERSON, Tomas, DALRYMPLE, Susan L, NATHANIEL BRENNEN, W, GERBER, Stephanie, HAMMERS, Hans, WISSING, Michel, KACHHAP, Sushant, JUN LUO, LI XING
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Association for Cancer Research 15.02.2013
• Subjects: Acetylation - drug effects; Allosteric Regulation; Animals; Antineoplastic agents; Basic Medicine; Biological and medical sciences; Blotting, Western; Cell Hypoxia; Cell Line, Tumor; Cell Survival - drug effects; Histone Deacetylases - chemistry; Histone Deacetylases - genetics; Histone Deacetylases - metabolism; Histones - metabolism; Human Umbilical Vein Endothelial Cells - drug effects; Human Umbilical Vein Endothelial Cells - metabolism; Humans; Hypoxia-Inducible Factor 1, alpha Subunit - genetics; Hypoxia-Inducible Factor 1, alpha Subunit - metabolism; Immunologi inom det medicinska området; Immunology in the medical area; Medical and Health Sciences; Medical sciences; Medicin och hälsovetenskap; Medicinska och farmaceutiska grundvetenskaper; Mice; Mice, Nude; Models, Molecular; Neoplasms - drug therapy; Neoplasms - genetics; Neoplasms - pathology; Pharmacology. Drug treatments; Prodrugs - pharmacology; Protein Binding - drug effects; Protein Structure, Tertiary; Quinolines - pharmacology; Quinolones; Repressor Proteins - chemistry; Repressor Proteins - genetics; Repressor Proteins - metabolism; RNA Interference; Signal Transduction - drug effects; Thapsigargin - pharmacology; Tumor Microenvironment - drug effects; Tumor Microenvironment - genetics; Tumors; Xenograft Model Antitumor Assays; Signal transduction; Allosteric regulation; Malignant tumor; Microenvironment; Survival; Tasquinimod; Cancer
• ISSN: 0008-5472; 1538-7445; 1538-7445
• DOI: 10.1158/0008-5472.CAN-12-2730

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 Zn(2+) 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-1α, 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. ©2012 AACR.