Abstract
Grb2-associated binder 2 (Gab2) serves as a critical amplifier in the signaling network of Bcr-Abl, the driver of chronic myeloid leukemia (CML). Despite the success of tyrosine kinase inhibitors (TKIs) in CML treatment, TKI resistance, caused by mutations in Bcr-Abl or aberrant activity of its network partners, remains a clinical problem. Using inducible expression and knockdown systems, we analyzed the role of Gab2 in Bcr-Abl signaling in human CML cells, especially with respect to TKI sensitivity. We show for the first time that Gab2 signaling protects CML cells from various Bcr-Abl inhibitors (imatinib, nilotinib, dasatinib and GNF-2), whereas Gab2 knockdown or haploinsufficiency leads to increased TKI sensitivity. We dissected the underlying molecular mechanism using various Gab2 mutants and kinase inhibitors and identified the Shp2/Ras/ERK and the PI3K/AKT/mTOR axes as the two critical signaling pathways. Gab2-mediated TKI resistance was associated with persistent phosphorylation of Gab2 Y452, a PI3K recruitment site, and consistent with this finding, the protective effect of Gab2 was completely abolished by the combination of dasatinib with the dual PI3K/mTOR inhibitor NVP-BEZ235. The identification of Gab2 as a novel modulator of TKI sensitivity in CML suggests that Gab2 could be exploited as a biomarker and therapeutic target in TKI-resistant disease.
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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14-3-3 Proteins / metabolism
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Adaptor Proteins, Signal Transducing / antagonists & inhibitors
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Adaptor Proteins, Signal Transducing / genetics
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Adaptor Proteins, Signal Transducing / metabolism*
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Adult
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Aged
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Antineoplastic Combined Chemotherapy Protocols
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Benzamides
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Blotting, Western
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Dasatinib
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Drug Resistance, Neoplasm*
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Female
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Follow-Up Studies
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Fusion Proteins, bcr-abl / antagonists & inhibitors*
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Humans
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Imatinib Mesylate
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Imidazoles / pharmacology
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Leukemia, Myelogenous, Chronic, BCR-ABL Positive / drug therapy*
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Leukemia, Myelogenous, Chronic, BCR-ABL Positive / metabolism
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MAP Kinase Signaling System / drug effects
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Male
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Middle Aged
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Phosphatidylinositol 3-Kinases / metabolism
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Phosphoinositide-3 Kinase Inhibitors
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Phosphorylation / drug effects
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Piperazines / pharmacology
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Prognosis
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Protein Kinase Inhibitors / pharmacology*
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Protein Tyrosine Phosphatase, Non-Receptor Type 11 / metabolism
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Proto-Oncogene Proteins c-akt / metabolism
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Pyrimidines / pharmacology
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Quinolines / pharmacology
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RNA, Small Interfering / genetics
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TOR Serine-Threonine Kinases / antagonists & inhibitors
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TOR Serine-Threonine Kinases / metabolism
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Thiazoles / pharmacology
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Tumor Cells, Cultured
Substances
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14-3-3 Proteins
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Adaptor Proteins, Signal Transducing
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Benzamides
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GAB2 protein, human
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Imidazoles
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Phosphoinositide-3 Kinase Inhibitors
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Piperazines
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Protein Kinase Inhibitors
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Pyrimidines
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Quinolines
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RNA, Small Interfering
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Thiazoles
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Imatinib Mesylate
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MTOR protein, human
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Fusion Proteins, bcr-abl
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Proto-Oncogene Proteins c-akt
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TOR Serine-Threonine Kinases
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Protein Tyrosine Phosphatase, Non-Receptor Type 11
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Dasatinib
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dactolisib