Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P15088 (mast cell)
 14,925 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Activating mutations of the activation loop of KIT are associated with certain human neoplasms, including the majority of patients with systemic mast cell disorders, as well as cases of seminoma, acute myelogenous leukemia (AML), and gastrointestinal stromal tumors (GISTs). The small-molecule tyrosine kinase inhibitor imatinib mesylate is a potent inhibitor of wild-type (WT) KIT and certain mutant KIT isoforms and has become the standard of care for treating patients with metastatic GIST. However, KIT activation loop mutations involving codon D816 that are typically found in AML, systemic mastocytosis, and seminoma are insensitive to imatinib mesylate (IC50 > 5-10 micromol/L), and acquired KIT activation loop mutations can be associated with imatinib mesylate resistance in GIST. Dasatinib (formerly BMS-354825) is a small-molecule, ATP-competitive inhibitor of SRC and ABL tyrosine kinases with potency in the low nanomolar range. Some small-molecule SRC/ABL inhibitors also have potency against WT KIT kinase. Therefore, we hypothesized that dasatinib might inhibit the kinase activity of both WT and mutant KIT isoforms. We report herein that dasatinib potently inhibits WT KIT and juxtamembrane domain mutant KIT autophosphorylation and KIT-dependent activation of downstream pathways important for cell viability and cell survival, such as Ras/mitogen-activated protein kinase, phosphoinositide 3-kinase/Akt, and Janus-activated kinase/signal transducers and activators of transcription. Furthermore, dasatinib is a potent inhibitor of imatinib-resistant KIT activation loop mutants and induces apoptosis in mast cell and leukemic cell lines expressing these mutations (potency against KIT D816Y >> D816F > D816V). Our studies suggest that dasatinib may have clinical efficacy against human neoplasms that are associated with gain-of-function KIT mutations.
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PMID:Dasatinib (BMS-354825), a dual SRC/ABL kinase inhibitor, inhibits the kinase activity of wild-type, juxtamembrane, and activation loop mutant KIT isoforms associated with human malignancies. 1639 63

Dasatinib has been reported to potently inhibit juxtamembrane domain mutant KIT(D816V) autophosphorylation and KIT-dependent activation of down stream signaling important for cell growth and survival of neoplastic cells. Additionally, dasatinib induced apoptosis in mast cell and leukemia cell lines expressing KIT(D816V). Here, we present the first case report of long-term hematologic and molecular remission achieved with combined treatment with chemotherapy and dasatinib in a patient with systemic mastocytosis (SM) and acute myeloid leukemia (AML) with mutant KIT(D816V) expression. A 50-year-old male presented with pancytopenia, organomegaly, lymphadenopathy, and lytic bone lesions in the pelvis. The patient was found to have systemic mastocytosis (SM) and acute myelogeneous leukemia (AML) positive for KIT(D816V) and therefore diagnosed with SM with an associated clonal hematological non-mast cell lineage disease (SM-AHNMD). Both primary CD34+ cells containing myeloblasts and CD34- cells containing mastocytes obtained from the diagnostic BM lost viability markedly by in vitro dasatinib treatment. In addition, dasatinib diminished activity of STAT5, STAT3, AKT and ERK and attenuated the levels of c-KIT. The patient achieved a hematologic complete remission (HCR) by two induction chemotherapies with residual mastocytes. Dasatinib (70mg PO bid, days 1-4) was added to consolidation treatments composed of four cycles of high dose cytarabine and was then continued as maintenance therapy (50mg PO bid). Periodic bone marrow (BM) aspirate/biopsies (eight over 18 months) were performed. The patient remained in HCR, and the mastocyte burden decreased by 50%. The bone lytic lesions improved. The KIT(D816V)mutation progressively decreased and became undetectable in the last three BM analyses. This result was confirmed by an independent laboratory showing a lack of c-KIT mutation in both CD34+ cells and CD34- cells in the last BM. No significant adverse effects of dasatinib occurred. Dasatinib has in vitro and in vivo efficacy in SM-AML patients with KIT(D816V) mutation. Along with chemotherapy, dasatinib should be considered in these patients particularly if they cannot undergo allogeneic stem cell transplantation for this poor prognostic AML.
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PMID:Chemotherapy and dasatinib induce long-term hematologic and molecular remission in systemic mastocytosis with acute myeloid leukemia with KIT D816V. 1898 3

Bruton's tyrosine kinase (BTK), a member of the TEC family of kinases, plays a crucial role in B-cell maturation and mast cell activation. Although the structures of the unphosphorylated mouse BTK kinase domain and the unphosphorylated and phosphorylated kinase domains of human ITK are known, understanding the kinase selectivity profiles of BTK inhibitors has been hampered by the lack of availability of a high resolution, ligand-bound BTK structure. Here, we report the crystal structures of the human BTK kinase domain bound to either Dasatinib (BMS-354825) at 1.9 A resolution or to 4-amino-5-(4-phenoxyphenyl)-7H-pyrrolospyrimidin- 7-yl-cyclopentane at 1.6 A resolution. This data provides information relevant to the development of small molecule inhibitors targeting BTK and the TEC family of nonreceptor tyrosine kinases. Analysis of the structural differences between the TEC and Src families of kinases near the Trp-Glu-Ile motif in the N-terminal region of the kinase domain suggests a mechanism of regulation of the TEC family members.
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PMID:Structures of human Bruton's tyrosine kinase in active and inactive conformations suggest a mechanism of activation for TEC family kinases. 2005 11

Several studies indicated that KIT mutation could cause ligand-independent activation of c-Kit receptor in canine mast cell tumor (MCT). The objective of this study was to investigate mechanisms of c-Kit receptor activation in various canine MCT cell lines. Four cell lines, HRMC (derived from cutaneous MCT), VIMC1 (visceral MCT), CoMS1 (visceral MCT) and CMMC1 (cutaneous MCT), were cultured in stem cell factor (SCF, a ligand of c-Kit receptor)-free medium and subjected to analyses of KIT mutation, c-Kit receptor phosphorylation, SCF expression and the effects of SCF stimulation. In addition, the SCF/c-Kit receptor autocrine mechanism was verified in HRMC cells. HRMC cells expressed wild type c-Kit receptor. Both VIMC1 and CoMS1 cells had the same one amino acid (AA) substitution in the extracellular domain of c-Kit receptor. CMMC1 cells had at least three variants of c-Kit receptor such as one AA deletion in the extracellular domain (variant A), one AA substitution in the extracellular domain as well as an internal tandem duplication in the juxtamembrane domain (variant B), and a nonsense mutation (variant C). Both mature and immature forms of c-Kit receptor were observed and the c-Kit receptors were phosphorylated in all cell lines. While both mature and immature forms of c-Kit receptor were substantially phosphorylated in CMMC1 cells, the immature form was slightly phosphorylated in other cell lines. Phosphorylation of c-Kit receptor in HRMC, VIMC1 and CoMS1 cells were enhanced by SCF stimulation whereas no enhancement was observed in CMMC1 cells. There was no effect of SCF stimulation on proliferation of all the cell lines. SCF protein was detectable in only HRMC cells although mRNA expression of SCF was detected in all the cell lines. A tyrosine kinase inhibitor Dasatinib (internal inhibitor) inhibited c-Kit receptor phosphorylation in HRMC cells whereas anti-canine SCF antibody (external inhibitor) had no inhibitory effect. Thus there could be no external SCF/c-Kit receptor autocrine mechanism whereas there could be an internal autocrine mechanism within HRMC cells. The results indicated that consistent c-Kit receptor phosphorylation could be caused by the stimulation with autocrine SCF in HRMC cells while it could be caused by functional mutations of KIT in VIMC1, CoMS1 and CMMC1 cells. As the four canine MCT cell lines had various aberrations associated with c-Kit receptor phosphorylation, KIT mutation and SCF expression, such molecular biological diversity might reflect the different biological behavior in canine MCT.
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PMID:Aberrant autophosphorylation of c-Kit receptor in canine mast cell tumor cell lines. 2059