scholarly journals Tumor-intrinsic and -extrinsic roles of c-Kit: mast cells as the primary off-target of tyrosine kinase inhibitors

Oncogene ◽  
2010 ◽  
Vol 30 (7) ◽  
pp. 757-769 ◽  
Author(s):  
P Pittoni ◽  
S Piconese ◽  
C Tripodo ◽  
M P Colombo
Keyword(s):  
Mast Cells ◽  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitors ◽  
Kinase Inhibitors

Novel thiazole amine class tyrosine kinase inhibitors induce apoptosis in human mast cells expressing D816V KIT mutation

2014 ◽  
Vol 353 (1) ◽  
pp. 115-123 ◽  
Author(s):  
Yanli Jin ◽  
Ke Ding ◽  
Deping Wang ◽  
Mengjie Shen ◽  
Jingxuan Pan
Keyword(s):  
Mast Cells ◽  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitors ◽  
Kinase Inhibitors ◽  
Kit Mutation ◽  
Human Mast Cells

The Kit-activating mutation D816V enhances stem cell factor–dependent chemotaxis

Blood ◽  
2001 ◽  
Vol 98 (4) ◽  
pp. 1195-1199 ◽  
Author(s):  
Marcia L. Taylor ◽  
Jaroslaw Dastych ◽  
Devinder Sehgal ◽  
Magnus Sundstrom ◽  
Gunnar Nilsson ◽  
...  
Keyword(s):  
Mast Cell ◽  
Stem Cell ◽  
Mast Cells ◽  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitors ◽  
Stem Cell Factor ◽  
Kinase Inhibitors ◽  
Jurkat Cells ◽  
Wild Type ◽  
Kit Mutation

The D816V mutation of c-kit has been detected in patients with mastocytosis. This mutation leads to constitutive tyrosine kinase activation of Kit. Because stem cell factor (SCF), the ligand for Kit (CD117+), is a chemoattractant for CD117+ cells and one feature of mastocytosis is an abnormal collection of mast cells in tissues derived from CD34+CD117+ mast cell precursors, the hypothesis was considered that the D816V mutation would enhance chemotaxis of these precursor cells. Constructs encoding wild-type Kit or Kit bearing the D816V mutation were transfected into Jurkat cells, labeled with Calcein-am, and migration to SCF assessed in the presence or absence of tyrosine kinase inhibitors. Chemotaxis to SCF was enhanced in D816V transfectants compared to wild-type Kit transfectants (P < .002). Migration of both transfectants was inhibited by tyrosine kinase inhibitors, although D816V transfectants were more sensitive. Chemotaxis was next performed on CD34+CD117+ circulating mast cell precursors obtained from patients with mastocytosis. Analysis of prechemotaxis and migrated cells showed that whereas less than 10% in the prechemotaxis sample had the D816V mutation, 40% to 80% of migrated cells had this mutation. These results demonstrate that the D816V Kit mutation enhances chemotaxis of CD117+ cells, offering one explanation for increased mast cells observed in tissues of patients with mastocytosis.

Synergistic Growth-Inhibitory Effects of Two Tyrosine Kinase Inhibitors, Dasatinib and PKC412, on Neoplastic Mast Cells Expressing the D816V-Mutated Oncogenic Variant of KIT.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 526-526 ◽  
Author(s):  
Karoline V. Gleixner ◽  
Matthias Mayerhofer ◽  
Karoline Sonneck ◽  
Alexander Gruze ◽  
Puchit Samorapoompichit ◽  
...  
Keyword(s):  
Mast Cell ◽  
Mast Cells ◽  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitors ◽  
Kinase Inhibitors ◽  
Systemic Mastocytosis ◽  
Cell Leukemia ◽  
Inhibitory Effects ◽  
Mast Cell Leukemia ◽  
Kit D816v

Abstract In a majority of all patients with systemic mastocytosis (SM) including aggressive SM and mast cell leukemia (MCL), neoplastic cells display the D816V-mutated variant of KIT. The respective oncoprotein, KIT-D816V, exhibits constitutive tyrosine kinase (TK) activity and has been implicated in malignant cell growth. Therefore, several attempts have been made to identify KIT-D816V-targeting drugs. We found that the TK-inhibitor dasatinib (BMS-354825) inhibits TK activity of wild type (wt) KIT and KIT-D816V in Ba/F3 cells with doxycycline-inducible KIT-expression. In addition, dasatinib was found to inhibit KIT D816V-induced cluster formation and viability in Ba/F3 cells as well as growth of HMC-1.1 cells (KIT-D816V-negative) and HMC-1.2 cells (KIT-D816V-positive). The effects of dasatinib on growth of HMC-1 cells were dose-dependent, with 100–1,000-fold higher IC50-values in cells harbouring KIT-D816V compared to cells lacking KIT-D816V. Furthermore, dasatinib was found to inhibit the growth of primary neoplastic mast cells in SM in all patients examined. The inhibitory effects of dasatinib in HMC-1 cells were found to be associated with apoptosis and a decrease in expression of CD2 and CD63 as determined by flow cytometry. In addition, dasatinib was found to cooperate with the tyrosine kinase inhibitors PKC412 (midostaurin), AMN107 (nilotinib), and STI571 (imatinib), as well as with 2CdA (cladribine) in producing growth-inhibition in neoplastic mast cells. In HMC-1.1 cells, all drug-interactions applied were found to be synergistic. By contrast, in HMC-1.2 cells, only the combinations “dasatinib+PKC412” and “dasatinib+2CdA” were found to produce synergistic effects. These drug-combinations may thus represent an interesting pharmacologic approach for the treatment of patients with aggressive systemic mastocytosis or mast cell leukemia.

Synergistic antiproliferative effects of KIT tyrosine kinase inhibitors on neoplastic canine mast cells

2007 ◽  
Vol 35 (10) ◽  
pp. 1510-1521 ◽  
Author(s):  
Karoline V. Gleixner ◽  
Laura Rebuzzi ◽  
Matthias Mayerhofer ◽  
Alexander Gruze ◽  
Emir Hadzijusufovic ◽  
...  
Keyword(s):  
Mast Cells ◽  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitors ◽  
Kinase Inhibitors ◽  
Antiproliferative Effects

scholarly journals Growth-inhibitory effects of four tyrosine kinase inhibitors on neoplastic feline mast cells exhibiting a Kit exon 8 ITD mutation

2009 ◽  
Vol 132 (2-4) ◽  
pp. 243-250 ◽  
Author(s):  
Emir Hadzijusufovic ◽  
Barbara Peter ◽  
Laura Rebuzzi ◽  
Christian Baumgartner ◽  
Karoline V. Gleixner ◽  
...  
Keyword(s):  
Mast Cells ◽  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitors ◽  
Kinase Inhibitors ◽  
Inhibitory Effects ◽  
Growth Inhibitory
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