2. Academic Validation
  3. Genetic resistance to JAK2 enzymatic inhibitors is overcome by HSP90 inhibition

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

Affiliation

  • 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.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-120604
    JAK2 Inhibitor