Genetic resistance to JAK2 enzymatic inhibitors is overcome by HSP90 inhibition Journal Article


Authors: Weigert, O.; Lane, A. A.; Bird, L.; Kopp, N.; Chapuy, B.; van Bodegom, D.; Toms, A. V.; Marubayashi, S.; Christie, A. L.; McKeown, M.; Paranal, R. M.; Bradner, J. E.; Yoda, A.; Gaul, C.; Vangrevelinghe, E.; Romanet, V.; Murakami, M.; Tiedt, R.; Ebel, N.; Evrot, E.; De Pover, A.; Régnier, C. H.; Erdmann, D.; Hofmann, F.; Eck, M. J.; Sallan, S. E.; Levine, R. L.; Kung, A. L.; Baffert, F.; Radimerski, T.; Weinstock, D. M.
Article Title: Genetic resistance to JAK2 enzymatic inhibitors is overcome by HSP90 inhibition
Abstract: Enzymatic inhibitors of Janus kinase 2 (JAK2) are in clinical development for the treatment of myeloproliferative neoplasms (MPNs), B cell acute lymphoblastic leukemia (B-ALL) with rearrangements of the cytokine receptor subunit cytokine receptor-like factor 2 (CRLF2), and other tumors with constitutive JAK2 signaling. In this study, we identify G935R, Y931C, and E864K mutations within the JAK2 kinase domain that confer resistance across a panel of JAK inhibitors, whether present in cis with JAK2 V617F (observed in MPNs) or JAK2 R683G (observed in B-ALL). G935R, Y931C, and E864K do not reduce the sensitivity of JAK2-dependent cells to inhibitors of heat shock protein 90 (HSP90), which promote the degradation of both wild-type and mutant JAK2. HSP90 inhibitors were 100-1,000-fold more potent against CRLF2-rearranged B-ALL cells, which correlated with JAK2 degradation and more extensive blockade of JAK2/STAT5, MAP kinase, and AKT signaling. In addition, the HSP90 inhibitor AUY922 prolonged survival of mice xenografted with primary human CRLF2-rearranged B-ALL further than an enzymatic JAK2 inhibitor. Thus, HSP90 is a promising therapeutic target in JAK2-driven cancers, including those with genetic resistance to JAK enzymatic inhibitors. © 2012 Weigert et al.
Keywords: immunohistochemistry; signal transduction; mitogen activated protein kinase; protein kinase b; controlled study; unclassified drug; overall survival; myeloproliferative disorder; janus kinase 2; nonhuman; flow cytometry; antineoplastic agent; animal cell; mouse; animal tissue; enzyme inhibition; bone marrow; enzyme degradation; animal experiment; animal model; in vivo study; antineoplastic activity; drug potency; in vitro study; enzyme activity; chemosensitivity; drug selectivity; acute lymphoblastic leukemia; gene rearrangement; heat shock protein 90 inhibitor; hematopoiesis; point mutation; stat5 protein; drug sensitivity; bioluminescence; spleen weight; heat shock transcription factor 1; hematocrit; 5 (2,4 dihydroxy 5 isopropylphenyl) 4 (4 morpholinomethylphenyl) 3 isoxazolecarboxylic acid ethylamide; cytokine receptor; janus kinase 2 inhibitor; genetic resistance; bvb 808; cytokine receptor like factor 2
Journal Title: Journal of Experimental Medicine
Volume: 209
Issue: 2
ISSN: 0022-1007
Publisher: Rockefeller University Press  
Date Published: 2012-02-13
Start Page: 259
End Page: 273
Language: English
DOI: 10.1084/jem.20111694
PROVIDER: scopus
PMCID: PMC3280877
PUBMED: 22271575
DOI/URL:
Notes: --- - "Export Date: 2 April 2012" - "CODEN: JEMEA" - "Source: Scopus"
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  1. Ross Levine
    620 Levine