1. Combined Targeting of JAK2 and Bcl-2/Bcl-xL to Cure Mutant JAK2-Driven Malignancies and Overcome Acquired Resistance to JAK2 Inhibitors
- Author
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Waibel, M, Solomon, VS, Knight, DA, Ralli, RA, Kim, SK, Banks, KM, Vidacs, E, Virely, C, Sia, KCS, Bracken, LS, Collins-Underwood, R, Drenberg, C, Ramsey, LB, Meyer, SC, Takiguchi, M, Dickins, RA, Levine, R, Ghysdael, J, Dawson, MA, Lock, RB, Mullighan, CG, Johnstone, RW, Waibel, M, Solomon, VS, Knight, DA, Ralli, RA, Kim, SK, Banks, KM, Vidacs, E, Virely, C, Sia, KCS, Bracken, LS, Collins-Underwood, R, Drenberg, C, Ramsey, LB, Meyer, SC, Takiguchi, M, Dickins, RA, Levine, R, Ghysdael, J, Dawson, MA, Lock, RB, Mullighan, CG, and Johnstone, RW
- 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.
- Published
- 2013