Genetic resistance to JAK2 enzymatic inhibitors is overcome by HSP90 inhibition

  • J Exp Med. 2012 Feb 13;209(2):259-73. doi: 10.1084/jem.20111694.
Oliver Weigert  1 ,  Andrew A Lane ,  Liat Bird ,  Nadja Kopp ,  Bjoern Chapuy ,  Diederik van Bodegom ,  Angela V Toms ,  Sachie Marubayashi ,  Amanda L Christie ,  Michael McKeown ,  Ronald M Paranal ,  James E Bradner ,  Akinori Yoda ,  Christoph Gaul ,  Eric Vangrevelinghe ,  Vincent Romanet ,  Masato Murakami ,  Ralph Tiedt ,  Nicolas Ebel ,  Emeline Evrot ,  Alain De Pover ,  Catherine H Régnier ,  Dirk Erdmann ,  Francesco Hofmann ,  Michael J Eck ,  Stephen E Sallan ,  Ross L Levine ,  Andrew L Kung ,  Fabienne Baffert ,  Thomas Radimerski ,  David M Weinstock
Affiliations
  • 1. Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA.
PMID: 22271575 DOI: 10.1084/jem.20111694
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.

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