Genetic resistance to JAK2 enzymatic inhibitors is overcome by HSP90 inhibition
Open Access
- 23 January 2012
- journal article
- Published by Rockefeller University Press in The Journal of Experimental Medicine
- Vol. 209 (2), 259-273
- https://doi.org/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.Keywords
This publication has 55 references indexed in Scilit:
- The JAK kinase inhibitor CP‐690,550 supresses the growth of human polycythemia vera cells carrying the JAK2V617F mutationCancer Science, 2008
- NVP-AUY922: a small molecule HSP90 inhibitor with potent antitumor activity in preclinical breast cancer modelsBreast Cancer Research, 2008
- NVP-AUY922: A Novel Heat Shock Protein 90 Inhibitor Active against Xenograft Tumor Growth, Angiogenesis, and MetastasisCancer Research, 2008
- Efficacy of TG101348, a Selective JAK2 Inhibitor, in Treatment of a Murine Model of JAK2V617F-Induced Polycythemia VeraCancer Cell, 2008
- Acquired resistance to tyrosine kinase inhibitors during cancer therapyCurrent Opinion in Genetics & Development, 2008
- Numerical gain and structural rearrangements of JAK2, identified by FISH, characterize both JAK2617V>F-positive and -negative patients with Ph-negative MPD, myelodysplasia, and B-lymphoid neoplasmsExperimental Hematology, 2007
- JAK2 inhibitor therapy in myeloproliferative disorders: rationale, preclinical studies and ongoing clinical trialsLeukemia, 2007
- Potentiation of antileukemic therapies by Smac mimetic, LBW242: effects on mutant FLT3-expressing cellsMolecular Cancer Therapeutics, 2007
- Heat shock protein 90: The cancer chaperoneJournal of Biosciences, 2007
- A potential role for HSP90 inhibitors in the treatment of JAK2 mutant-positive diseases as demonstrated using quantitative flow cytometryLeukemia & Lymphoma, 2007