Akahane, Koshi, Sanda, Takaomi, Mansour, Marc R., Radimerski, Thomas, Weinstock, David M., Letai, Anthony and Look, Thomas (2016) HSP90 Inhibition Leads to Degradation of the TYK2 Kinase and Apoptotic Cell Death in T-Cell Acute Lymphoblastic Leukemia. Leukemia, 30 (1). pp. 219-228. ISSN 1476-5551; 0887-6924

Abstract

Abstract
We have previously shown that TYK2 tyrosine kinase signaling through its downstream effector phospho-STAT1 (p-STAT1) acts to upregulate BCL2, which mediates the aberrant survival of T-cell acute lymphoblastic leukemia (T-ALL) cells. In this study, we demonstrate that pharmacological inhibition of heat shock protein 90 (HSP90) with a small-molecule inhibitor, NVP-AUY922 (AUY922), leads to the rapid degradation of TYK2 and apoptosis in T-ALL cells. STAT1 protein expression levels are unaffected by AUY922 treatment, but p-STAT1 (Tyr 701) levels rapidly become undetectable, consistent with a block in signaling downstream of TYK2. BCL2 expression is downregulated after AUY922 treatment, and although this effect is necessary for AUY922-induced apoptosis, it is not sufficient because many T-ALL cell lines are resistant to BCL2 inhibition by ABT-199. Our study reveals that unlike ABT-199, AUY922 also upregulates the pro-apoptotic proteins BIM and BAD, and that the synergistic combination of downregulation of BCL2 and upregulation of BH3-only proteins explains the potent pro-apoptotic activity of AUY922 in T-ALL cells.

Significance
Despite advances in the therapy for patients with T-ALL, nearly 25% of children and greater than 50% of adults still succumb to this disease, indicating that further therapeutic improvements are urgently needed. Our study shows that pharmacological inhibition of HSP90 by a small-molecule inhibitor currently in clinical trials efficiently induces apoptosis in T-ALL cells through the combined effects of blocking the TYK2-STAT1-BCL2 pro-survival pathway and simultaneously upregulating the BIM and BAD pro-apoptotic BH3-only proteins.

Item Type:	Article
Date Deposited:	12 Oct 2016 00:45
Last Modified:	12 Oct 2016 00:45
URI:	https://oak.novartis.com/id/eprint/24542