Genetic resistance to JAK2 enzymatic inhibitors is overcome by HSP90 inhibition

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Author
Weigert, Oliver
Bird, Liat
Kopp, Nadja
van Bodegom, Diederik
Marubayashi, Sachie
Christie, Amanda L.
Paranal, Ronald M.
Gaul, Christoph
Vangrevelinghe, Eric
Romanet, Vincent
Murakami, Masato
Tiedt, Ralph
Ebel, Nicolas
Evrot, Emeline
De Pover, Alain
Régnier, Catherine H.
Erdmann, Dirk
Hofmann, Francesco
Levine, Ross L.
Baffert, Fabienne
Radimerski, Thomas
Kung, Andrew
Note: Order does not necessarily reflect citation order of authors.
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https://doi.org/10.1084/jem.20111694Metadata
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Weigert, Oliver, Andrew A. Lane, Liat Bird, Nadja Kopp, Bjoern Chapuy, Diederik van Bodegom, Angela V. Toms, et al. 2012. Genetic resistance to JAK2 enzymatic inhibitors is overcome by HSP90 inhibition. The Journal of Experimental Medicine 209(2): 259-273.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.Other Sources
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3280877/pdf/Terms of Use
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