title: Axl Blockade by BGB324 Inhibits BCR-ABL Tyrosine Kinase Inhibitor-Sensitive and -Resistant Chronic Myeloid Leukemia.
abstract: Purpose:BCR-ABL kinase inhibitors are employed successfully for chronic myeloid leukemia (CML) treatment. However, resistant disease and persistence of BCR-ABL1-independent leukemia stem and progenitor cells (LSPC) remain clinical challenges. The receptor tyrosine kinase Axl can mediate survival and therapy resistance of different cancer cells. We investigated the therapeutic potential of Axl inhibition in CML.Experimental Design:We used primary cells from patients with CML and TKI-sensitive and -resistant BCR-ABL1+CML cell lines and a novel ponatinib-resistant cell line KCL-22 PonR. We analyzed the effects of genetic and pharmacologic Axl blockade by the small-molecule Axl inhibitor BGB324in vitroandin vivoIn BCR-ABL1-unmutated cells, we also investigated BGB324 in combination with imatinib.Results:We demonstrate overexpression of Axl receptor tyrosine kinase in primary cells of patients with CML compared with healthy individuals and a further increase of Axl expression in BCR-ABL TKI-resistant patients. We show that Axl blockage decreased growth of BCR-ABL TKI-sensitive CML cells including CD34+cells and exerts additive effects with imatinib via inhibition of Stat5 activation. BGB324 also inhibits BCR-ABL TKI-resistant cells, including T315I-mutated and ponatinib-resistant primary cells. BGB324 exerted therapeutic effects in BCR-ABL1 T315I-mutated and ponatinib-resistant preclinical mouse models. Notably, BGB324 does not inhibit BCR-ABL1 and consequently inhibits CML independent of BCR-ABL1 mutational status.Conclusions:Our data show that Axl inhibition has therapeutic potential in BCR-ABL TKI-sensitive as well as -resistant CML and support the need for clinical trials.Clin Cancer Res; 23(9); 2289-300. ©2016 AACR.
authors.affiliation: Department of Hematology and Oncology with Sections BMT and Pneumology, Hubertus Wald Tumorzentrum, University Comprehensive Cancer Center Hamburg, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.|Department of Tumor Biology, Center of Experimental Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Isabel
authors.initials: I
authors.lastname: Ben-Batalla
authors.affiliation: Department of Hematology and Oncology with Sections BMT and Pneumology, Hubertus Wald Tumorzentrum, University Comprehensive Cancer Center Hamburg, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.|Department of Tumor Biology, Center of Experimental Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Robert
authors.initials: R
authors.lastname: Erdmann
authors.affiliation: Paul O'Gorman Leukaemia Research Centre, College of Medical, Veterinary & Life Sciences, Institute of Cancer Sciences, University of Glasgow, Glasgow, Scotland, United Kingdom.
authors.forename: Heather
authors.initials: H
authors.lastname: Jørgensen
authors.affiliation: Paul O'Gorman Leukaemia Research Centre, College of Medical, Veterinary & Life Sciences, Institute of Cancer Sciences, University of Glasgow, Glasgow, Scotland, United Kingdom.
authors.forename: Rebecca
authors.initials: R
authors.lastname: Mitchell
authors.affiliation: Hematology/Oncology, Jena University Hospital, Jena, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Ernst
authors.affiliation: Department of Hematology and Oncology with Sections BMT and Pneumology, Hubertus Wald Tumorzentrum, University Comprehensive Cancer Center Hamburg, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Gunhild
authors.initials: G
authors.lastname: von Amsberg
authors.affiliation: Department of Hematology and Oncology with Sections BMT and Pneumology, Hubertus Wald Tumorzentrum, University Comprehensive Cancer Center Hamburg, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Philippe
authors.initials: P
authors.lastname: Schafhausen
authors.affiliation: Department of Hematology and Oncology with Sections BMT and Pneumology, Hubertus Wald Tumorzentrum, University Comprehensive Cancer Center Hamburg, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.|Department of Tumor Biology, Center of Experimental Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Janna L
authors.initials: JL
authors.lastname: Velthaus
authors.affiliation: Paul O'Gorman Leukaemia Research Centre, College of Medical, Veterinary & Life Sciences, Institute of Cancer Sciences, University of Glasgow, Glasgow, Scotland, United Kingdom.
authors.forename: Stephen
authors.initials: S
authors.lastname: Rankin
authors.affiliation: Department of Haematology, Molecular and Clinical Cancer Medicine, Royal Liverpool University Hospital, Liverpool, United Kingdom.
authors.forename: Richard E
authors.initials: RE
authors.lastname: Clark
authors.affiliation: Department of Hematology, Oncology, Hemostaseology, and Stem Cell Transplantation, Faculty of Medicine, RWTH Aachen University, Aachen, Germany.
authors.forename: Steffen
authors.initials: S
authors.lastname: Koschmieder
authors.affiliation: Department of Hematology and Oncology with Sections BMT and Pneumology, Hubertus Wald Tumorzentrum, University Comprehensive Cancer Center Hamburg, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Alexander
authors.initials: A
authors.lastname: Schultze
authors.affiliation: Department of Haematology, Milton Keynes Hospital NHS Foundation Trust, Milton Keynes, United Kingdom.
authors.forename: Subir
authors.initials: S
authors.lastname: Mitra
authors.affiliation: Centre for Human Genetics, University Hospitals Leuven, Leuven, Belgium.
authors.forename: Peter
authors.initials: P
authors.lastname: Vandenberghe
authors.affiliation: Department of Hematology, Oncology, Hemostaseology, and Stem Cell Transplantation, Faculty of Medicine, RWTH Aachen University, Aachen, Germany.
authors.forename: Tim H
authors.initials: TH
authors.lastname: Brümmendorf
authors.affiliation: Laboratory of Angiogenesis and Neurovascular Link, Vesalius Research Center, VIB, Leuven, Belgium.|Laboratory of Angiogenesis and Neurovascular Link, Vesalius Research Center, KU Leuven, Leuven, Belgium.
authors.forename: Peter
authors.initials: P
authors.lastname: Carmeliet
authors.affiliation: Hematology/Oncology, Jena University Hospital, Jena, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Hochhaus
authors.affiliation: Department of Tumor Biology, Center of Experimental Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Klaus
authors.initials: K
authors.lastname: Pantel
authors.affiliation: Department of Hematology and Oncology with Sections BMT and Pneumology, Hubertus Wald Tumorzentrum, University Comprehensive Cancer Center Hamburg, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Carsten
authors.initials: C
authors.lastname: Bokemeyer
authors.affiliation: Wolfson Wohl Cancer Research Centre, College of Medical, Veterinary & Life Sciences, Institute of Cancer Sciences, University of Glasgow, Glasgow, Scotland, United Kingdom.
authors.forename: G Vignir
authors.initials: GV
authors.lastname: Helgason
authors.affiliation: Paul O'Gorman Leukaemia Research Centre, College of Medical, Veterinary & Life Sciences, Institute of Cancer Sciences, University of Glasgow, Glasgow, Scotland, United Kingdom.
authors.forename: Tessa L
authors.initials: TL
authors.lastname: Holyoake
authors.affiliation: Department of Hematology and Oncology with Sections BMT and Pneumology, Hubertus Wald Tumorzentrum, University Comprehensive Cancer Center Hamburg, University Medical Center Hamburg-Eppendorf, Hamburg, Germany. s.loges@uke.uni-hamburg.de.|Department of Tumor Biology, Center of Experimental Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Sonja
authors.initials: S
authors.lastname: Loges
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001567:Benzocycloheptenes / Q000008:administration & dosage*; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D016044:Fusion Proteins, bcr-abl / Q000037:antagonists & inhibitors / Q000235:genetics*; D006801:Humans; D000068877:Imatinib Mesylate / Q000008:administration & dosage; D007093:Imidazoles / Q000008:administration & dosage; D020014:K562 Cells; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D051379:Mice; D009154:Mutation; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors / Q000235:genetics*; D011724:Pyridazines / Q000008:administration & dosage; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics*; D054852:Small Molecule Libraries / Q000008:administration & dosage; D014230:Triazoles / Q000008:administration & dosage*; D000094963:Axl Receptor Tyrosine Kinase
chemical_list: D001567:Benzocycloheptenes; D007093:Imidazoles; D047428:Protein Kinase Inhibitors; D011518:Proto-Oncogene Proteins; D011724:Pyridazines; D054852:Small Molecule Libraries; D014230:Triazoles; C548378:bemcentinib; C545373:ponatinib; D000068877:Imatinib Mesylate; D020794:Receptor Protein-Tyrosine Kinases; D016044:Fusion Proteins, bcr-abl; D000094963:Axl Receptor Tyrosine Kinase