Genetic resistance to JAK2 enzymatic inhibitors is overcome by HSP90 inhibition
نویسندگان
چکیده
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.
منابع مشابه
The interplay between inhibition of JAK2 and HSP90
A recent article by Weigert et al. published in The Journal of Experimental Medicine described the in vitro generation of synthetic mutations in Janus kinase 2 (JAK 2) that decreased the potency of JAK2 (or JAK1/JAK2) inhibitors in artificial systems. The authors found that heat shock protein 90 (HSP90) inhibitors circumvented the potency shift and suggested that HSP90 inhibition may abrogate J...
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PURPOSE We determined the activity of hsp90 inhibitor, and/or Janus-activated kinase 2 (JAK2) tyrosine kinase inhibitor (TKI), against JAK2-V617F-expressing cultured mouse (Ba/F3-JAK2-V617F) and human (HEL92.1.7 and UKE-1) or primary human CD34(+) myeloproliferative neoplasm (MPN) cells. EXPERIMENTAL DESIGN Following exposure to the hsp90 inhibitor AUY922 and/or JAK2-TKI TG101209, the levels ...
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عنوان ژورنال:
دوره 209 شماره
صفحات -
تاریخ انتشار 2012