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Molecular targets for therapy

HSP90 inhibition leads to degradation of the TYK2 kinase and apoptotic cell death in T-cell acute lymphoblastic leukemia


We previously found that tyrosine kinase 2 (TYK2) signaling through its downstream effector phospho-STAT1 acts to upregulate BCL2, which in turn mediates aberrant survival of T-cell acute lymphoblastic leukemia (T-ALL) cells. Here we show that pharmacologic inhibition of heat shock protein 90 (HSP90) with a small-molecule inhibitor, NVP-AUY922 (AUY922), leads to rapid degradation of TYK2 and apoptosis in T-ALL cells. STAT1 protein levels were not affected by AUY922 treatment, but phospho-STAT1 (Tyr-701) levels rapidly became undetectable, consistent with a block in signaling downstream of TYK2. BCL2 expression was downregulated after AUY922 treatment, and although this effect was necessary for AUY922-induced apoptosis, it was not sufficient because many T-ALL cell lines were resistant to ABT-199, a specific inhibitor of BCL2. Unlike ABT-199, AUY922 also upregulated the proapoptotic proteins BIM and BAD, whose increased expression was required for AUY922-induced apoptosis. Thus, the potent cytotoxicity of AUY922 involves the synergistic combination of BCL2 downregulation coupled with upregulation of the proapoptotic proteins BIM and BAD. This two-pronged assault on the mitochondrial apoptotic machinery identifies HSP90 inhibitors as promising drugs for targeting the TYK2-mediated prosurvival signaling axis in T-ALL cells.

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We thank Dr Anthony Letai for helpful discussions and critical review. We also thank John R Gilbert for critical review of the manuscript and editorial suggestions, and Drs Julia Etchin and Cherry Ng-Dombrowsky for helpful advice and assistance. This research was supported by fellowships and grants from the Leukemia & Lymphoma Society (CDP5014-14; KA), the Lauri Strauss Leukemia Foundation (2013 Discovery research grant; KA) and NPO Corporation the Gold Ribbon Network of the Japan (KA), Bridge grant from Alex’s Lemonade Stand Foundation, and grants from the National Cancer Institute (5R01CA176746 and 5P01CA109901) (ATL). MRM is funded by the Claudia Adams Barr Innovative Basic Science Research Program and the Kay Kendall Leukaemia Trust of the UK. TS is supported by a grant from the National Research Foundation, Prime Minister’s Office, Singapore under its NRF Fellowship Programme (Award No. NRF-NRFF2013-02). DMW is supported by a Translational Research Program award from the Leukemia & Lymphoma Society. We also thank Novartis for the compound NVP-AUY922.

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Correspondence to A T Look.

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Dr Radimerski is an employee of Novartis. Dr Weinstock receives research funding and is a consultant for Novartis. The remaining authors declare no conflict of interest.

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Akahane, K., Sanda, T., Mansour, M. et al. HSP90 inhibition leads to degradation of the TYK2 kinase and apoptotic cell death in T-cell acute lymphoblastic leukemia. Leukemia 30, 219–228 (2016).

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