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 KC, 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
- Subjects
- Animals, Apoptosis drug effects, Apoptosis Regulatory Proteins genetics, Bcl-2-Like Protein 11, Biphenyl Compounds pharmacology, Cell Line, Tumor, Cell Survival, Gene Expression Profiling, Humans, Janus Kinase 2 genetics, Membrane Proteins genetics, Mice, Mice, Inbred C57BL, Mice, Inbred NOD, Mice, SCID, Neoplasm Transplantation, Nitriles, Nitrophenols pharmacology, Piperazines pharmacology, Proto-Oncogene Proteins genetics, Pyrazoles pharmacology, Pyrimidines pharmacology, Signal Transduction drug effects, Sulfonamides pharmacology, Transplantation, Heterologous, bcl-X Protein genetics, Drug Resistance, Neoplasm, Janus Kinase 2 antagonists & inhibitors, Precursor T-Cell Lymphoblastic Leukemia-Lymphoma drug therapy, bcl-X Protein antagonists & 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 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., (Copyright © 2013 The Authors. Published by Elsevier Inc. All rights reserved.)
- Published
- 2013
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