Axl Blockade by BGB324 Inhibits BCR-ABL Tyrosine Kinase Inhibitor-Sensitive and -Resistant Chronic Myeloid Leukemia

• Published in: Clinical cancer research Vol. 23; no. 9; pp. 2289 - 2300
• Main Authors: Ben-Batalla, Isabel, Erdmann, Robert, Jørgensen, Heather, Mitchell, Rebecca, Ernst, Thomas, von Amsberg, Gunhild, Schafhausen, Philippe, Velthaus, Janna L, Rankin, Stephen, Clark, Richard E, Koschmieder, Steffen, Schultze, Alexander, Mitra, Subir, Vandenberghe, Peter, Brümmendorf, Tim H, Carmeliet, Peter, Hochhaus, Andreas, Pantel, Klaus, Bokemeyer, Carsten, Helgason, G Vignir, Holyoake, Tessa L, Loges, Sonja
• Format: Journal Article
• Language: English
• Published: United States American Association for Cancer Research Inc 01.05.2017
• Subjects: Abl protein; Animal models; Animals; Apoptosis - drug effects; Axl protein; BCR protein; Benzocycloheptenes - administration & dosage; Cancer; CD34 antigen; Cells (biology); Chronic myeloid leukemia; Clinical trials; Drug Resistance, Neoplasm - genetics; Enzyme inhibitors; Experimental design; Fusion protein; Fusion Proteins, bcr-abl - antagonists & inhibitors; Fusion Proteins, bcr-abl - genetics; Humans; Imatinib; Imatinib Mesylate - administration & dosage; Imidazoles - administration & dosage; In vivo methods and tests; Inhibition; Inhibitors; K562 Cells; Kinases; Leukemia; Leukemia, Myelogenous, Chronic, BCR-ABL Positive - drug therapy; Leukemia, Myelogenous, Chronic, BCR-ABL Positive - genetics; Leukemia, Myelogenous, Chronic, BCR-ABL Positive - pathology; Medical research; Medical treatment; Mice; Mutation; Myeloid leukemia; Patients; Pharmacology; Progenitor cells; Protein Kinase Inhibitors - administration & dosage; Protein-tyrosine kinase receptors; Proto-Oncogene Proteins - antagonists & inhibitors; Proto-Oncogene Proteins - genetics; Pyridazines - administration & dosage; Receptor Protein-Tyrosine Kinases - antagonists & inhibitors; Receptor Protein-Tyrosine Kinases - genetics; Small Molecule Libraries - administration & dosage; Stat5 protein; Stem cells; Triazoles - administration & dosage; Tyrosine
• DOI: 10.1158/1078-0432.CCR-16-1930
• ISSN: 1078-0432

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. 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 BGB324 and In BCR-ABL1-unmutated cells, we also investigated BGB324 in combination with imatinib. 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. 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. .