Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Article
  • Published:

Molecular targets for therapy

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

Leukemia volume 30, pages 219–228 (2016)Cite this article

Subjects

Abstract

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.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6
Figure 7

Similar content being viewed by others

References

  1. Goldberg JM, Silverman LB, Levy DE, Dalton VK, Gelber RD, Lehmann L et al. Childhood T-cell acute lymphoblastic leukemia: the Dana-Farber Cancer Institute acute lymphoblastic leukemia consortium experience. J Clin Oncol 2003; 21: 3616–3622.

    Article  Google Scholar 

  2. Marks DI, Paietta EM, Moorman AV, Richards SM, Buck G, DeWald G et al. T-cell acute lymphoblastic leukemia in adults: clinical features, immunophenotype, cytogenetics, and outcome from the large randomized prospective trial (UKALL XII/ECOG 2993). Blood 2009; 114: 5136–5145.

    Article  CAS  Google Scholar 

  3. Oudot C, Auclerc MF, Levy V, Porcher R, Piguet C, Perel Y et al. Prognostic factors for leukemic induction failure in children with acute lymphoblastic leukemia and outcome after salvage therapy: the FRALLE 93 study. J Clin Oncol 2008; 26: 1496–1503.

    Article  CAS  Google Scholar 

  4. Schrappe M, Hunger SP, Pui CH, Saha V, Gaynon PS, Baruchel A et al. Outcomes after induction failure in childhood acute lymphoblastic leukemia. N Engl J Med 2012; 366: 1371–1381.

    Article  CAS  Google Scholar 

  5. Aifantis I, Raetz E, Buonamici S . Molecular pathogenesis of T-cell leukaemia and lymphoma. Nat Rev Immunol 2008; 8: 380–390.

    Article  CAS  Google Scholar 

  6. Sanda T, Tyner JW, Gutierrez A, Ngo VN, Glover J, Chang BH et al. TYK2-STAT1-BCL2 pathway dependence in T-cell acute lymphoblastic leukemia. Cancer Discov 2013; 3: 564–577.

    Article  CAS  Google Scholar 

  7. Taipale M, Krykbaeva I, Koeva M, Kayatekin C, Westover KD, Karras GI et al. Quantitative analysis of HSP90-client interactions reveals principles of substrate recognition. Cell 2012; 150: 987–1001.

    Article  CAS  Google Scholar 

  8. Caldas-Lopes E, Cerchietti L, Ahn JH, Clement CC, Robles AI, Rodina A et al. Hsp90 inhibitor PU-H71, a multimodal inhibitor of malignancy, induces complete responses in triple-negative breast cancer models. Proc Natl Acad Sci USA 2009; 106: 8368–8373.

    Article  CAS  Google Scholar 

  9. Wandinger SK, Richter K, Buchner J . The Hsp90 chaperone machinery. J Biol Chem 2008; 283: 18473–18477.

    Article  CAS  Google Scholar 

  10. Taipale M, Jarosz DF, Lindquist S . HSP90 at the hub of protein homeostasis: emerging mechanistic insights. Nat Rev Mol Cell Biol 2010; 11: 515–528.

    Article  CAS  Google Scholar 

  11. Trepel J, Mollapour M, Giaccone G, Neckers L . Targeting the dynamic HSP90 complex in cancer. Nat Rev Cancer 2010; 10: 537–549.

    Article  CAS  Google Scholar 

  12. Isaacs JS, Xu W, Neckers L . Heat shock protein 90 as a molecular target for cancer therapeutics. Cancer Cell 2003; 3: 213–217.

    Article  CAS  Google Scholar 

  13. Jhaveri K, Taldone T, Modi S, Chiosis G . Advances in the clinical development of heat shock protein 90 (Hsp90) inhibitors in cancers. Biochim Biophys Acta 2012; 1823: 742–755.

    Article  CAS  Google Scholar 

  14. Neckers L, Workman P . Hsp90 molecular chaperone inhibitors: are we there yet? Clin Cancer Res 2012; 18: 64–76.

    Article  CAS  Google Scholar 

  15. Marubayashi S, Koppikar P, Taldone T, Abdel-Wahab O, West N, Bhagwat N et al. HSP90 is a therapeutic target in JAK2-dependent myeloproliferative neoplasms in mice and humans. J Clin Invest 2010; 120: 3578–3593.

    Article  CAS  Google Scholar 

  16. Weigert O, Lane AA, Bird L, Kopp N, Chapuy B, van Bodegom D et al. Genetic resistance to JAK2 enzymatic inhibitors is overcome by HSP90 inhibition. J Exp Med 2012; 209: 259–273.

    Article  CAS  Google Scholar 

  17. Eccles SA, Massey A, Raynaud FI, Sharp SY, Box G, Valenti M et al. NVP-AUY922: a novel heat shock protein 90 inhibitor active against xenograft tumor growth, angiogenesis, and metastasis. Cancer Res 2008; 68: 2850–2860.

    Article  CAS  Google Scholar 

  18. Whitesell L, Bagatell R, Falsey R . The stress response: implications for the clinical development of hsp90 inhibitors. Curr Cancer Drug Targets 2003; 3: 349–358.

    Article  CAS  Google Scholar 

  19. Mesa RA, Loegering D, Powell HL, Flatten K, Arlander SJ, Dai NT et al. Heat shock protein 90 inhibition sensitizes acute myelogenous leukemia cells to cytarabine. Blood 2005; 106: 318–327.

    Article  CAS  Google Scholar 

  20. Anderson NM, Harrold I, Mansour MR, Sanda T, McKeown M, Nagykary N et al. BCL2-specific inhibitor ABT-199 synergizes strongly with cytarabine against the early immature LOUCY cell line but not more-differentiated T-ALL cell lines. Leukemia 2014; 28: 1145–1148.

    Article  CAS  Google Scholar 

  21. Ni Chonghaile T, Roderick JE, Glenfield C, Ryan J, Sallan SE, Silverman LB et al. Maturation stage of T-cell acute lymphoblastic leukemia determines BCL-2 versus BCL-XL dependence and sensitivity to ABT-199. Cancer Discov 2014; 4: 1074–1087.

    Article  Google Scholar 

  22. Peirs S, Matthijssens F, Goossens S, Van de Walle I, Ruggero K, de Bock CE et al. ABT-199 mediated inhibition of BCL-2 as a novel therapeutic strategy in T-cell acute lymphoblastic leukemia. Blood 2014; 124: 3738–3747.

    Article  CAS  Google Scholar 

  23. Van Vlierberghe P, Ambesi-Impiombato A, Perez-Garcia A, Haydu JE, Rigo I, Hadler M et al. ETV6 mutations in early immature human T cell leukemias. J Exp Med 2011; 208: 2571–2579.

    Article  CAS  Google Scholar 

  24. Certo M, Del Gaizo Moore V, Nishino M, Wei G, Korsmeyer S, Armstrong SA et al. Mitochondria primed by death signals determine cellular addiction to antiapoptotic BCL-2 family members. Cancer cell 2006; 9: 351–365.

    Article  CAS  Google Scholar 

  25. Chao DT, Linette GP, Boise LH, White LS, Thompson CB, Korsmeyer SJ . Bcl-XL and Bcl-2 repress a common pathway of cell death. J Exp Med 1995; 182: 821–828.

    Article  CAS  Google Scholar 

  26. Bonni A, Brunet A, West AE, Datta SR, Takasu MA, Greenberg ME . Cell survival promoted by the Ras-MAPK signaling pathway by transcription-dependent and -independent mechanisms. Science 1999; 286: 1358–1362.

    Article  CAS  Google Scholar 

  27. Knoechel B, Roderick JE, Williamson KE, Zhu J, Lohr JG, Cotton MJ et al. An epigenetic mechanism of resistance to targeted therapy in T cell acute lymphoblastic leukemia. Nat Genet 2014; 46: 364–370.

    Article  CAS  Google Scholar 

  28. Coustan-Smith E, Mullighan CG, Onciu M, Behm FG, Raimondi SC, Pei D et al. Early T-cell precursor leukaemia: a subtype of very high-risk acute lymphoblastic leukaemia. Lancet Oncol 2009; 10: 147–156.

    Article  CAS  Google Scholar 

  29. Bouillet P, Metcalf D, Huang DC, Tarlinton DM, Kay TW, Kontgen F et al. Proapoptotic Bcl-2 relative Bim required for certain apoptotic responses, leukocyte homeostasis, and to preclude autoimmunity. Science 1999; 286: 1735–1738.

    Article  CAS  Google Scholar 

  30. Opferman JT, Letai A, Beard C, Sorcinelli MD, Ong CC, Korsmeyer SJ . Development and maintenance of B and T lymphocytes requires antiapoptotic MCL-1. Nature 2003; 426: 671–676.

    Article  CAS  Google Scholar 

  31. Reynolds C, Roderick JE, Labelle JL, Bird G, Mathieu R, Bodaar K et al. Repression of BIM mediates survival signaling by MYC and AKT in high-risk T-cell acute lymphoblastic leukemia. Leukemia 2014; 28: 1819–1827.

    Article  CAS  Google Scholar 

  32. Paraiso KH, Haarberg HE, Wood E, Rebecca VW, Chen YA, Xiang Y et al. The HSP90 inhibitor XL888 overcomes BRAF inhibitor resistance mediated through diverse mechanisms. Clin Cancer Res 2012; 18: 2502–2514.

    Article  CAS  Google Scholar 

  33. Haarberg HE, Paraiso KH, Wood E, Rebecca VW, Sondak VK, Koomen JM et al. Inhibition of Wee1, AKT, and CDK4 underlies the efficacy of the HSP90 inhibitor XL888 in an in vivo model of NRAS-mutant melanoma. Mol Cancer Ther 2013; 12: 901–912.

    Article  CAS  Google Scholar 

  34. Sessa C, Shapiro GI, Bhalla KN, Britten C, Jacks KS, Mita M et al. First-in-human phase I dose-escalation study of the HSP90 inhibitor AUY922 in patients with advanced solid tumors. Clin Cancer Res 2013; 19: 3671–3680.

    Article  CAS  Google Scholar 

  35. Jensen MR, Schoepfer J, Radimerski T, Massey A, Guy CT, Brueggen J et al. NVP-AUY922: a small molecule HSP90 inhibitor with potent antitumor activity in preclinical breast cancer models. Breast Cancer Res 2008; 10: R33.

    Article  Google Scholar 

Download references

Acknowledgements

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.

Author information

Authors and Affiliations

  1. Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA

    K Akahane, T Sanda, M R Mansour & A T Look

  2. Cancer Science Institute of Singapore, National University of Singapore, Singapore

    T Sanda

  3. Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore

    T Sanda

  4. Department of Haematology, UCL Cancer Institute, University College London, London, UK

    M R Mansour

  5. Disease Area Oncology, Novartis Institutes for BioMedical Research, Basel, Switzerland

    T Radimerski

  6. Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA

    D J DeAngelo & D M Weinstock

  7. Division of Hematology/Oncology, Children's Hospital, Boston, MA, USA

    A T Look

Authors
  1. K Akahane
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. T Sanda
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. M R Mansour
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. T Radimerski
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. D J DeAngelo
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. D M Weinstock
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. A T Look
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to A T Look.

Ethics declarations

Competing interests

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.

Additional information

Supplementary Information accompanies this paper on the Leukemia website

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

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). https://doi.org/10.1038/leu.2015.222

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/leu.2015.222

This article is cited by

Search

Advanced search

Quick links