Combined targeting of JAK2 and Bcl-2/Bcl-xL to cure mutant JAK2-driven malignancies and overcome acquired resistance to JAK2 inhibitors.

Waibel, Michaela; Solomon, Vanessa S; Knight, Deborah A; Ralli, Rachael A; Kim, Sang-Kyu; Banks, Kellie-Marie; Vidacs, Eva; Virely, Clemence; Sia, Keith C S; Bracken, Lauryn S; Collins-Underwood, Racquel; Drenberg, Christina; Ramsey, Laura B; Meyer, Sara C.; Takiguchi, Megumi; Dickins, Ross A; Levine, Ross; Ghysdael, Jacques; Dawson, Mark A; Lock, Richard B; ... (2013). Combined targeting of JAK2 and Bcl-2/Bcl-xL to cure mutant JAK2-driven malignancies and overcome acquired resistance to JAK2 inhibitors. Cell reports, 5(4), pp. 1047-1059. Cell Press 10.1016/j.celrep.2013.10.038

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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 pathways were constitutively active, and gene expression profiling of TEL-JAK2 T-ALL cells revealed the upregulation 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 and mouse JAK2 mutant tumors. Moreover, combined targeting of JAK2 and Bcl-2/Bcl-xL was able to 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 effective and provides a clearly superior therapeutic benefit than targeting just one node. Therefore, we have defined a potentially curative treatment for hematological malignancies expressing constitutively active JAK2.

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