Combined Targeting of JAK2 and Bcl-2/Bcl-xL to Cure Mutant JAK2-Driven Malignancies and Overcome Acquired Resistance to JAK2 Inhibitors Journal Article
| Authors: | Waibel, M.; Solomon, V. S.; Knight, D. A.; Ralli, R. A.; Kim, S. K.; Banks, K. M.; Vidacs, E.; Virely, C.; Sia, K. C. S.; Bracken, L. S.; Collins-Underwood, R.; Drenberg, C.; Ramsey, L. B.; Meyer, S. C.; Takiguchi, M.; Dickins, R. A.; Levine, R.; Ghysdael, J.; Dawson, M. A.; Lock, R. B.; Mullighan, C. G.; Johnstone, R. W. |
| Article Title: | Combined Targeting of JAK2 and Bcl-2/Bcl-xL to Cure Mutant JAK2-Driven Malignancies and Overcome Acquired Resistance to JAK2 Inhibitors |
| Abstract: | To design rational therapies for JAK2-driven hematological malignancies, we functionally dissected the key survival pathways downstream of hyperactive JAK2. In tumors driven by mutant JAK2, Stat1, Stat3, Stat5, and the Pi3k and Mek/Erk pathwayswere constitutively active, and gene expressionprofiling of TEL-JAK2 T-ALL cells revealed theupregulation of prosurvival Bcl-2 family genes. Combining the Bcl-2/Bcl-xL inhibitor ABT-737 with JAK2 inhibitors mediated prolonged disease regressions and cures in mice bearing primary human andmouse JAK2 mutant tumors. Moreover, combined targeting of JAK2 and Bcl-2/Bcl-xL was ableto circumvent and overcome acquired resistance to single-agent JAK2 inhibitor treatment. Thus, inhibiting the oncogenic JAK2 signaling network at two nodal points, at the initiating stage (JAK2) and the effector stage (Bcl-2/Bcl-xL), is highly effectiveand provides a clearly superior therapeutic benefitthan targeting just one node. Therefore, we have defined a potentially curative treatment for hematological malignancies expressing constitutively active JAK2. © 2013 The Authors. |
| Journal Title: | Cell Reports |
| Volume: | 5 |
| Issue: | 4 |
| ISSN: | 2211-1247 |
| Publisher: | Cell Press |
| Date Published: | 2013-11-27 |
| Start Page: | 1047 |
| End Page: | 1059 |
| Language: | English |
| DOI: | 10.1016/j.celrep.2013.10.038 |
| PROVIDER: | scopus |
| PMCID: | PMC3898474 |
| PUBMED: | 24268771 |
| DOI/URL: | |
| Notes: | Export Date: 2 January 2014 -- Source: Scopus |
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