title: Axitinib and sorafenib are potent in tyrosine kinase inhibitor resistant chronic myeloid leukemia cells.
abstract: BACKGROUND
  Chronic myeloid leukemia (CML) is driven by the fusion kinase Bcr-Abl. Bcr-Abl tyrosine kinase inhibitors (TKIs), such as imatinib mesylate (IM), revolutionized CML therapy. Nevertheless, about 20 % of CMLs display primary or acquired TKI resistance. TKI resistance can be either caused by mutations within the Bcr-Abl kinase domain or by aberrant signaling by its effectors, e.g. Lyn or Gab2. Bcr-Abl mutations are frequently observed in TKI resistance and can only in some cases be overcome by second line TKIs. In addition, we have previously shown that the formation of Gab2 complexes can be regulated by Bcr-Abl and that Gab2 signaling counteracts the efficacy of four distinct Bcr-Abl inhibitors. Therefore, TKI resistance still represents a challenge for disease management and alternative therapies are urgently needed.
  
  
  RESULTS
  Using different CML cell lines and models, we identified the clinically approved TKIs sorafenib (SF) and axitinib (AX) as drugs overcoming the resistance mediated by the Bcr Abl(T315I) mutant as well as the one mediated by Gab2 and Lyn(Y508F). In addition, we demonstrated that AX mainly affects the Bcr-Abl/Grb2/Gab2 axis, whereas SF seems to act independently of the fusion kinase and most likely by blocking signaling pathways up- and downstream of Gab2.
  
  
  CONCLUSIONS
  We demonstrate that SF and AX show potency in various and mechanistically distinct scenarios of TKI resistance, including Bcr-Abl(T315I) as well as Lyn- and Gab2-mediated resistances. Our data invites for further evaluation und consideration of these inhibitors in the treatment of TKI resistant CML.
authors.affiliation: Institute of Molecular Medicine and Cell Research (IMMZ), Faculty of Medicine, University of Freiburg, Freiburg, Germany. Sebastian.Halbach@sgbm.uni-freiburg.de.|Faculty of Biology, University of Freiburg, Freiburg, Germany. Sebastian.Halbach@sgbm.uni-freiburg.de.|Spemann Graduate School of Biology and Medicine, University of Freiburg, Freiburg, Germany. Sebastian.Halbach@sgbm.uni-freiburg.de.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Halbach
authors.affiliation: Freiburg Institute for Advanced Studies (FRIAS), and Center for Biological Systems Analysis (ZBSA), University of Freiburg, Freiburg, Germany. zehan.hu@hotmail.com.|Department of Dermatology, Medical Center, University of Freiburg, Freiburg, Germany. zehan.hu@hotmail.com.
authors.forename: Zehan
authors.initials: Z
authors.lastname: Hu
authors.affiliation: Freiburg Institute for Advanced Studies (FRIAS), and Center for Biological Systems Analysis (ZBSA), University of Freiburg, Freiburg, Germany. christine.gretzmeier@medizin.uni-freiburg.de.|Department of Dermatology, Medical Center, University of Freiburg, Freiburg, Germany. christine.gretzmeier@medizin.uni-freiburg.de.
authors.forename: Christine
authors.initials: C
authors.lastname: Gretzmeier
authors.affiliation: Institute of Molecular Medicine and Cell Research (IMMZ), Faculty of Medicine, University of Freiburg, Freiburg, Germany. julia.ellermann@hotmail.com.|Faculty of Biology, University of Freiburg, Freiburg, Germany. julia.ellermann@hotmail.com.
authors.forename: Julia
authors.initials: J
authors.lastname: Ellermann
authors.affiliation: Institute of Molecular Medicine and Cell Research (IMMZ), Faculty of Medicine, University of Freiburg, Freiburg, Germany. franziska.woehrle@gmail.com.|Faculty of Biology, University of Freiburg, Freiburg, Germany. franziska.woehrle@gmail.com.|Spemann Graduate School of Biology and Medicine, University of Freiburg, Freiburg, Germany. franziska.woehrle@gmail.com.|BIOSS Centre for Biological Signalling Studies, University of Freiburg, Freiburg, Germany. franziska.woehrle@gmail.com.
authors.forename: Franziska U
authors.initials: FU
authors.lastname: Wöhrle
authors.affiliation: Freiburg Institute for Advanced Studies (FRIAS), and Center for Biological Systems Analysis (ZBSA), University of Freiburg, Freiburg, Germany. joern.dengjel@medizin.uni-freiburg.de.|BIOSS Centre for Biological Signalling Studies, University of Freiburg, Freiburg, Germany. joern.dengjel@medizin.uni-freiburg.de.|Department of Dermatology, Medical Center, University of Freiburg, Freiburg, Germany. joern.dengjel@medizin.uni-freiburg.de.
authors.forename: Jörn
authors.initials: J
authors.lastname: Dengjel
authors.affiliation: Institute of Molecular Medicine and Cell Research (IMMZ), Faculty of Medicine, University of Freiburg, Freiburg, Germany. tilman.brummer@zbsa.uni-freiburg.de.|BIOSS Centre for Biological Signalling Studies, University of Freiburg, Freiburg, Germany. tilman.brummer@zbsa.uni-freiburg.de.|Deutsches Konsortium für Translationale Krebsforschung (DKTK) and Comprehensive Cancer Center Freiburg, University Medical Center, Freiburg, Germany. tilman.brummer@zbsa.uni-freiburg.de.
authors.forename: Tilman
authors.initials: T
authors.lastname: Brummer
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism; D000077784:Axitinib; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm; D016044:Fusion Proteins, bcr-abl / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology*; D007191:Indazoles / Q000494:pharmacology*; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D009154:Mutation; D009536:Niacinamide / Q000031:analogs & derivatives* / Q000494:pharmacology; D010671:Phenylurea Compounds / Q000494:pharmacology*; D017354:Point Mutation; D060066:Protein Interaction Maps / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D000077157:Sorafenib; D019061:src-Family Kinases / Q000235:genetics / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C490895:GAB2 protein, human; D007093:Imidazoles; D007191:Indazoles; D010671:Phenylurea Compounds; D047428:Protein Kinase Inhibitors; D009536:Niacinamide; D000077157:Sorafenib; D000077784:Axitinib; D016044:Fusion Proteins, bcr-abl; C060902:lyn protein-tyrosine kinase; D019061:src-Family Kinases