Genetic resistance to JAK2 enzymatic inhibitors is overcome by HSP90 inhibition
van Bodegom, Diederik
Christie, Amanda L.
Paranal, Ronald M.
De Pover, Alain
Régnier, Catherine H.
Levine, Ross L.
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CitationWeigert, 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.
AbstractEnzymatic 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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