Growth-inhibitory effects of four tyrosine kinase inhibitors on neoplastic feline mast cells exhibiting a Kit exon 8 ITD mutation.
Systemic mastocytosis (SM) in felines is a rare neoplasm defined by increased growth and accumulation of immature mast cells (MC) in various organs including the spleen. Although in many cases splenectomy is an effective approach, relapses may occur. In these patients, treatment options are limited. Recent data suggest that various Kit tyrosine kinase inhibitors (TKI) interfere with growth of neoplastic MC in humans. In the current study, we examined the effects of four TKI, imatinib, midostaurin, nilotinib, and dasatinib, on growth of spleen-derived feline neoplastic MC in three SM patients. Expression of Kit in neoplastic MC was confirmed by flow cytometry and/or Western blotting. In all three cases, a 12-bp internal tandem duplication in exon 8, resulting in a four amino acid-insertion between residues Thr418 and His419 in Kit, was detectable. As assessed by (3)H-thymidine incorporation experiments, all four TKI were found to inhibit the growth of feline neoplastic MC in a dose-dependent manner. The growth-inhibitory TKI effects were found to be associated with morphologic signs of apoptosis in MC. In conclusion, various Kit-targeting TKI can inhibit the in vitro growth and survival of feline neoplastic MC in SM.
Hadzijusufovic
Emir
E
Department of Companion Animals and Horses, Clinic for Internal Medicine and Infectious Diseases, University of Veterinary Medicine Vienna, Austria.
Peter
Barbara
B
Rebuzzi
Laura
L
Baumgartner
Christian
C
Gleixner
Karoline V
KV
Gruze
Alexander
A
Thaiwong
Tuddow
T
Pickl
Winfried F
WF
Yuzbasiyan-Gurkan
Vilma
V
Willmann
Michael
M
Valent
Peter
P
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001483:Base Sequence; D001549:Benzamides; D002371:Cat Diseases / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D002415:Cats; D049109:Cell Proliferation / Q000187:drug effects; D017931:DNA Primers / Q000235:genetics; D000069439:Dasatinib; D005091:Exons; D005260:Female; D006801:Humans; D000068877:Imatinib Mesylate; D066298:In Vitro Techniques; D008297:Male; D008407:Mast Cells / Q000187:drug effects / Q000473:pathology; D034721:Mastocytosis, Systemic / Q000188:drug therapy / Q000201:enzymology / Q000235:genetics / Q000662:veterinary*; D008969:Molecular Sequence Data; D009154:Mutation; D010766:Phosphorylation; D010879:Piperazines / Q000627:therapeutic use; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D019009:Proto-Oncogene Proteins c-kit / Q000037:antagonists & inhibitors* / Q000235:genetics* / Q000378:metabolism; D011743:Pyrimidines / Q000627:therapeutic use; D019311:Staurosporine / Q000031:analogs & derivatives / Q000627:therapeutic use; D020080:Tandem Repeat Sequences; D013844:Thiazoles / Q000627:therapeutic use
D001549:Benzamides; D017931:DNA Primers; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D013844:Thiazoles; D000068877:Imatinib Mesylate; D019009:Proto-Oncogene Proteins c-kit; C498826:nilotinib; D019311:Staurosporine; C059539:midostaurin; D000069439:Dasatinib