Abstract
Development of resistance to kinase inhibitors remains a clinical challenge. Kinase domain mutations are a common mechanism of resistance in chronic myeloid leukemia (CML), yet the mechanism of resistance in the absence of mutations remains unclear. We tested proteins from the bone marrow microenvironment and found that FGF2 promotes resistance to imatinib in vitro. Fibroblast growth factor 2 (FGF2) was uniquely capable of promoting growth in both short- and long-term assays through the FGF receptor 3/RAS/c-RAF/mitogen-activated protein kinase pathway. Resistance could be overcome with ponatinib, a multikinase inhibitor that targets BCR-ABL and FGF receptor. Clinically, we identified CML patients without kinase domain mutations who were resistant to multiple ABL kinase inhibitors and responded to ponatinib treatment. In comparison to CML patients with kinase domain mutations, these patients had increased FGF2 in their bone marrow when analyzed by immunohistochemistry. Moreover, FGF2 in the marrow decreased concurrently with response to ponatinib, further suggesting that FGF2-mediated resistance is interrupted by FGF receptor inhibition. These results illustrate the clinical importance of ligand-induced resistance to kinase inhibitors and support an approach of developing rational inhibitor combinations to circumvent resistance.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Antineoplastic Agents / pharmacology
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Antineoplastic Agents / therapeutic use
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Benzamides / pharmacology
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Cell Line, Tumor
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Drug Resistance, Neoplasm / genetics*
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Fibroblast Growth Factor 2 / chemistry
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Fibroblast Growth Factor 2 / genetics*
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Fibroblast Growth Factor 2 / metabolism
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Humans
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Imatinib Mesylate
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Imidazoles / pharmacology*
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Imidazoles / therapeutic use
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K562 Cells
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Leukemia, Myelogenous, Chronic, BCR-ABL Positive / drug therapy
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Leukemia, Myelogenous, Chronic, BCR-ABL Positive / genetics*
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Leukemia, Myelogenous, Chronic, BCR-ABL Positive / metabolism
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Mitogen-Activated Protein Kinases / metabolism
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Mutation*
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Piperazines / pharmacology
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Protein Interaction Domains and Motifs / genetics*
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Protein Kinase Inhibitors / pharmacology*
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Protein Kinase Inhibitors / therapeutic use
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Proto-Oncogene Proteins c-abl / antagonists & inhibitors
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Proto-Oncogene Proteins c-abl / metabolism
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Proto-Oncogene Proteins c-raf / metabolism
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Proto-Oncogene Proteins p21(ras) / metabolism
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Pyridazines / pharmacology*
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Pyridazines / therapeutic use
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Pyrimidines / pharmacology
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Receptor, Fibroblast Growth Factor, Type 3 / antagonists & inhibitors
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Receptor, Fibroblast Growth Factor, Type 3 / metabolism
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Signal Transduction
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Tumor Microenvironment / drug effects
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Tumor Microenvironment / genetics
Substances
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Antineoplastic Agents
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Benzamides
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Imidazoles
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Piperazines
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Protein Kinase Inhibitors
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Pyridazines
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Pyrimidines
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Fibroblast Growth Factor 2
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ponatinib
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Imatinib Mesylate
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Receptor, Fibroblast Growth Factor, Type 3
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Proto-Oncogene Proteins c-abl
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Proto-Oncogene Proteins c-raf
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Mitogen-Activated Protein Kinases
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Proto-Oncogene Proteins p21(ras)