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

Waibel, M.Solomon, V.Knight, D.Ralli, R.Kim, S.Banks, K.Vidacs, E.Virely, C.Sia, K.Bracken, L.Collins-Underwood, R.Drenberg, C.Ramsey, L.Meyer, S.Takiguchi, M.Dickins, R.Levine, R.Ghysdael, J.Dawson, M.Lock, R.et al.2017-03-022017-03-022013Cell reports, 2013; 5(4):1047-10592211-12472211-1247http://hdl.handle.net/2440/103601To 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.en©2013 The Authors, This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial-No Derivative Works License, which permits non-commercial use, distribution, and reproduction in any medium, provided the original author and source are credited.Cell Line, TumorAnimalsMice, Inbred C57BLMice, Inbred NODHumansMiceMice, SCIDSulfonamidesBiphenyl CompoundsNitrilesNitrophenolsPiperazinesPyrazolesPyrimidinesMembrane ProteinsProto-Oncogene ProteinsTransplantation, HeterologousGene Expression ProfilingNeoplasm TransplantationSignal TransductionApoptosisCell SurvivalDrug Resistance, NeoplasmApoptosis Regulatory Proteinsbcl-X ProteinJanus Kinase 2Precursor T-Cell Lymphoblastic Leukemia-LymphomaBcl-2-Like Protein 11Combined targeting of JAK2 and Bcl-2/Bcl-xL to cure mutant JAK2-driven malignancies and overcome acquired resistance to JAK2 inhibitorsJournal article003006121110.1016/j.celrep.2013.10.0380003282660000192-s2.0-84888430616277148Mullighan, C. [0000-0002-1871-1850]