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 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.

scholarly journals Tyrosine Kinase Inhibitors Are Promising Therapeutic Tools for Cats with HER2-Positive Mammary Carcinoma

Pharmaceutics ◽  
2021 ◽  
Vol 13 (3) ◽  
pp. 346
Author(s):  
Andreia Gameiro ◽  
Filipe Almeida ◽  
Catarina Nascimento ◽  
Jorge Correia ◽  
Fernando Ferreira
Keyword(s):  
Breast Cancer ◽  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitors ◽  
Cell Lines ◽  
Mammary Carcinoma ◽  
Kinase Inhibitors ◽  
Tyrosine Kinase Domain ◽  
Her2 Positive ◽  
Resistance To Therapy ◽  
Antiproliferative Effects

Feline mammary carcinoma (FMC) is a common neoplasia in cat, being HER2-positive the most prevalent subtype. In woman’s breast cancer, tyrosine kinase inhibitors (TKi) are used as a therapeutic option, by blocking the phosphorylation of the HER2 tyrosine kinase domain. Moreover, clinical trials demonstrated that TKi produce synergistic antiproliferative effects in combination with mTOR inhibitors, overcoming resistance to therapy. Thus, to uncover new chemotherapeutic strategies for cats, the antiproliferative effects of two TKi (lapatinib and neratinib), and their combination with a mTOR inhibitor (rapamycin), were evaluated in FMC cell lines (CAT-M, FMCp and FMCm) and compared with a human breast cancer cell line (SkBR-3). Results revealed that both TKi induced antiproliferative effects in all feline cell lines, by blocking the phosphorylation of EGFR members and its downstream effectors. Furthermore, combined treatments with rapamycin presented synergetic antiproliferative effects. Additionally, the DNA sequence of the her2 TK domain (exons 18 to 20) was determined in 40 FMC tissue samples, and despite several mutations were found none of them were described as inducing resistance to therapy. Altogether, our results demonstrated that TKi and combined protocols may be useful in the treatment of cats with mammary carcinomas, and that TKi-resistant FMC are rare.

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.

Antiproliferative Effects of Tyrosine Kinase Inhibitors (Tyrphostins) on Human Bladder and Renal Carcinoma Cells

1995 ◽  
Vol 59 (6) ◽  
pp. 675-680 ◽  
Author(s):  
Netta Sion-Vardy ◽  
Daniel Vardy ◽  
Ulrich Rodeck ◽  
Csaba Kari ◽  
Robert M. Levin ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitors ◽  
Renal Carcinoma ◽  
Kinase Inhibitors ◽  
Carcinoma Cells ◽  
Human Bladder ◽  
Antiproliferative Effects ◽  
Renal Carcinoma Cells

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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