TY - JOUR
T1 - Tasquinimod is an allosteric modulator of HDAC4 survival signaling within the compromised cancer microenvironment
AU - Isaacs, John T.
AU - Antony, Lizamma
AU - Dalrymple, Susan L.
AU - Brennen, W. Nathaniel
AU - Gerber, Stephanie
AU - Hammers, Hans
AU - Wissing, Michel
AU - Kachhap, Sushant
AU - Luo, Jun
AU - Xing, Li
AU - Bjork, Per
AU - Olsson, Anders
AU - Bjork, Anders
AU - Leanderson, Tomas
PY - 2013/1/15
Y1 - 2013/1/15
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84874342427&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84874342427&partnerID=8YFLogxK
U2 - 10.1158/0008-5472.CAN-12-2730
DO - 10.1158/0008-5472.CAN-12-2730
M3 - Article
C2 - 23149916
AN - SCOPUS:84874342427
SN - 0008-5472
VL - 73
SP - 1386
EP - 1399
JO - Cancer Research
JF - Cancer Research
IS - 4
ER -