Genetic resistance to JAK2 enzymatic inhibitors is overcome by HSP90 inhibition

O Weigert, AA Lane, L Bird, N Kopp… - Journal of experimental …, 2012 - rupress.org
O Weigert, AA Lane, L Bird, N Kopp, B Chapuy, D van Bodegom, AV Toms, S Marubayashi…
Journal of experimental medicine, 2012rupress.org
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 …
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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