title: EXEL-0862, a novel tyrosine kinase inhibitor, induces apoptosis in vitro and ex vivo in human mast cells expressing the KIT D816V mutation.
abstract: Gain-of-function mutations of the receptor tyrosine kinase KIT play a key role in the pathogenesis of systemic mastocytosis (SM), gastrointestinal stromal tumors (GISTs), and some cases of acute myeloid leukemia (AML). Whereas KIT juxtamembrane domain mutations seen in most patients with GIST are highly sensitive to imatinib, the kinase activation loop mutant D816V, frequently encountered in SM, hampers the binding ability of imatinib. We investigated the inhibitory activity of the novel tyrosine kinase inhibitor EXEL-0862 against 2 subclones of human mast cell line-1 (HMC-1)-HMC-1.1, harboring the juxtamembrane domain mutation V560G, and HMC-1.2, carrying V560G and the activation loop mutation D816V, found in more than 80% of patients with SM. EXEL-0862 inhibited the phosphorylation of KIT in a dose-dependent manner and decreased cell proliferation in both mast cell lines with higher activity against HMC-1.2 cells. The phosphorylation of KIT-dependent signal transducer and activator of transcription-3 (STAT3) and STAT5 was abrogated upon exposure to nanomolar concentrations of EXEL-0862. In addition, EXEL-0862 induced a time- and dose-dependent proapoptotic effect in both mast cell lines and caused a significant reduction in mast-cell content in bone marrow samples from patients with SM harboring D816V and from those without the D816V mutation. We conclude that EXEL-0862 is active against KIT activation loop mutants and is a promising candidate for the treatment of patients with SM and other KIT-driven malignancies harboring active site mutations.
authors.affiliation: The University of Texas M D Anderson Cancer Center, Unit 428, 1515 Holcombe Blvd, Houston, TX 77030, USA.
authors.forename: Jingxuan
authors.initials: J
authors.lastname: Pan
authors.forename: Alfonso
authors.initials: A
authors.lastname: Quintás-Cardama
authors.forename: Hagop M
authors.initials: HM
authors.lastname: Kantarjian
authors.forename: Cem
authors.initials: C
authors.lastname: Akin
authors.forename: Taghi
authors.initials: T
authors.lastname: Manshouri
authors.forename: Peter
authors.initials: P
authors.lastname: Lamb
authors.forename: Jorge E
authors.initials: JE
authors.lastname: Cortes
authors.forename: Ayalew
authors.initials: A
authors.lastname: Tefferi
authors.forename: Francis J
authors.initials: FJ
authors.lastname: Giles
authors.forename: Srdan
authors.initials: S
authors.lastname: Verstovsek
mesh_terms: D000368:Aged; D019943:Amino Acid Substitution; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D001853:Bone Marrow / Q000473:pathology; D053148:Caspase 3 / Q000378:metabolism; D053453:Caspase 9 / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects; D002478:Cells, Cultured / Q000187:drug effects; D002999:Clone Cells / Q000187:drug effects / Q000201:enzymology; D004789:Enzyme Activation / Q000187:drug effects; D005260:Female; D006801:Humans; D020128:Inhibitory Concentration 50; D008297:Male; D008407:Mast Cells / Q000187:drug effects* / Q000201:enzymology; D034721:Mastocytosis, Systemic / Q000201:enzymology / Q000473:pathology*; D008564:Membrane Potentials / Q000187:drug effects; D008875:Middle Aged; D008928:Mitochondria / Q000187:drug effects; D020125:Mutation, Missense; D010766:Phosphorylation / Q000187:drug effects; D017354:Point Mutation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D019009:Proto-Oncogene Proteins c-kit / Q000187:drug effects* / Q000235:genetics; D050796:STAT3 Transcription Factor / Q000378:metabolism; D050799:STAT5 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D050799:STAT5 Transcription Factor; D019009:Proto-Oncogene Proteins c-kit; D053148:Caspase 3; D053453:Caspase 9