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Genetic resistance to JAK2 enzymatic inhibitors is overcome by HSP90 inhibition

Weigert, Oliver and Bird, Liat and Kopp, Nadja and Lane A, Andrew and Chapuy, Bjoern and van Bodegom, Diederik and Toms, Angela and Marubayashi, Sachie and McKeown, Michael and Bradner E., James and Yoda, Akinori and Gaul, Christoph and Vangrevelinghe, Eric and Romanet, Vincent and Murakami, Masato and Ebel, Nicolas and De Pover, Alain and Regnier, Catherine and Hofmann, Francesco and eck, Michael and Ross L, Levine and Kung, Andrew and Baffert, Fabienne and Radimerski, Thomas and Weinstock M, David (2012) Genetic resistance to JAK2 enzymatic inhibitors is overcome by HSP90 inhibition. Journal of experimental medicine, 209 (2). pp. 259-273. ISSN 0022-1007

Abstract

Enzymatic inhibitors of Janus kinase 2 (JAK2) are in clinical development for the treatment of myelproliferative neoplasms (MPNs) and other diseases with dependence on JAK2. We and others recently identified rearrangements of the CRLF2 cytokine receptor, which signals through JAK2, in a subset of B-cell acute lymphoblastic leukemias (B-ALL) 1-4. Here we show that B-ALL cells with CRLF2-rearrangements maintain JAK2 signaling in the presence of therapeutic concentrations of enzymatic JAK2 inhibitors. In contrast, destabilization and degradation of JAK2 through inhibition of heat shock protein 90 (HSP90) effectively blocks CRLF2 signaling and prolongs survival in mice xenografted with primary human B-ALL. We identify G935R, Y931C and E864K mutations within the JAK2 kinase domain that confer resistance to a panel of JAK2 inhibitors, whether involving JAK2 V617F (observed in MPNs) signaling through the erythropoietin receptor or JAK2 R683G (observed in B-ALL) signaling through CRLF2. None of the mutations affect sensitivity to HSP90 inhibitors. Thus, resistance to JAK2 enzymatic inhibitors can either result from persistent JAK2 signaling or kinase domain mutations and is overcome by inhibition of HSP90.

Item Type: Article
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Date Deposited: 13 Oct 2015 13:15
Last Modified: 13 Oct 2015 13:15
URI: https://oak.novartis.com/id/eprint/5493

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