title: Gab2 signaling in chronic myeloid leukemia cells confers resistance to multiple Bcr-Abl inhibitors.
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.
authors.affiliation: Centre for Biological Systems Analysis, Albert-Ludwigs-University of Freiburg, Freiburg, Germany.
authors.forename: F U
authors.initials: FU
authors.lastname: Wöhrle
authors.forename: S
authors.initials: S
authors.lastname: Halbach
authors.forename: K
authors.initials: K
authors.lastname: Aumann
authors.forename: S
authors.initials: S
authors.lastname: Schwemmers
authors.forename: S
authors.initials: S
authors.lastname: Braun
authors.forename: P
authors.initials: P
authors.lastname: Auberger
authors.forename: D
authors.initials: D
authors.lastname: Schramek
authors.forename: J M
authors.initials: JM
authors.lastname: Penninger
authors.forename: S
authors.initials: S
authors.lastname: Laßmann
authors.forename: M
authors.initials: M
authors.lastname: Werner
authors.forename: C F
authors.initials: CF
authors.lastname: Waller
authors.forename: H L
authors.initials: HL
authors.lastname: Pahl
authors.forename: R
authors.initials: R
authors.lastname: Zeiser
authors.forename: R J
authors.initials: RJ
authors.lastname: Daly
authors.forename: T
authors.initials: T
authors.lastname: Brummer
mesh_terms: D048948:14-3-3 Proteins / Q000378:metabolism; D048868:Adaptor Proteins, Signal Transducing / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols; D001549:Benzamides; D015153:Blotting, Western; D000069439:Dasatinib; D019008:Drug Resistance, Neoplasm; D005260:Female; D005500:Follow-Up Studies; D016044:Fusion Proteins, bcr-abl / Q000037:antagonists & inhibitors*; D006801:Humans; D000068877:Imatinib Mesylate; D007093:Imidazoles / Q000494:pharmacology; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy* / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008297:Male; D008875:Middle Aged; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation / Q000187:drug effects; D010879:Piperazines / Q000494:pharmacology; D011379:Prognosis; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11 / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011743:Pyrimidines / Q000494:pharmacology; D011804:Quinolines / Q000494:pharmacology; D034741:RNA, Small Interfering / Q000235:genetics; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D013844:Thiazoles / Q000494:pharmacology; D014407:Tumor Cells, Cultured
chemical_list: D048948:14-3-3 Proteins; D048868:Adaptor Proteins, Signal Transducing; D001549:Benzamides; D000069439:Dasatinib; D016044:Fusion Proteins, bcr-abl; D000068877:Imatinib Mesylate; D007093:Imidazoles; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; D051057:Proto-Oncogene Proteins c-akt; D011743:Pyrimidines; D011804:Quinolines; D034741:RNA, Small Interfering; D058570:TOR Serine-Threonine Kinases; D013844:Thiazoles; C490895:GAB2 protein, human; C546842:MTOR protein, human; C531198:dactolisib