Receptor tyrosine kinase (c-Kit) inhibitors: a potential therapeutic target in cancer cells

Abstract

c-Kit, a receptor tyrosine kinase, is involved in intracellular signaling, and the mutated form of c-Kit plays a crucial role in occurrence of some cancers. The function of c-Kit has led to the concept that inhibiting c-Kit kinase activity can be a target for cancer therapy. The promising results of inhibition of c-Kit for treatment of cancers have been observed in some cancers such as gastrointestinal stromal tumor, acute myeloid leukemia, melanoma, and other tumors, and these results have encouraged attempts toward improvement of using c-Kit as a capable target for cancer therapy. This paper presents the findings of previous studies regarding c-Kit as a receptor tyrosine kinase and an oncogene, as well as its gene targets and signaling pathways in normal and cancer cells. The c-Kit gene location, protein structure, and the role of c-Kit in normal cell have been discussed. Comprehending the molecular mechanism underlying c-Kit-mediated tumorogenesis is consequently essential and may lead to the identification of future novel drug targets. The potential mechanisms by which c-Kit induces cellular transformation have been described. This study aims to elucidate the function of c-Kit for future cancer therapy. In addition, it has c-Kit inhibitor drug properties and their functions have been listed in tables and demonstrated in schematic pictures. This review also has collected previous studies that targeted c-Kit as a novel strategy for cancer therapy. This paper further emphasizes the advantages of this approach, as well as the limitations that must be addressed in the future. Finally, although c-Kit is an attractive target for cancer therapy, based on the outcomes of treatment of patients with c-Kit inhibitors, it is unlikely that Kit inhibitors alone can lead to cure. It seems that c-Kit mutations alone are not sufficient for tumorogenesis, but do play a crucial role in cancer occurrence.

miRNAs as Key Players in the Management of Cutaneous Melanoma

“…KIT is often altered in mucosal malignant melanomas, where it activates intracellular signaling cascades, including the MAPK, PI3K, and JAK-STAT pathways. The most common c-KIT mutations in melanoma are L676P and K642E [19]. Trials conducted with Imatinib mesylate, an inhibitor of KIT and other RTKs, in patients with c-KIT-mutant melanoma, have reported median times to disease progression of approximately 3 months that are significantly lower than the time to progression when Imatinib is used to treat gastrointestinal stromal tumors (GIST) (median time to progression of 18 months).…”

“…Trials conducted with Imatinib mesylate, an inhibitor of KIT and other RTKs, in patients with c-KIT-mutant melanoma, have reported median times to disease progression of approximately 3 months that are significantly lower than the time to progression when Imatinib is used to treat gastrointestinal stromal tumors (GIST) (median time to progression of 18 months). Despite the presence of the same mutation, it is unclear why there is such a difference in response between KIT-mutant melanoma and GIST, suggesting that there may be other pathways involved in this treatment resistance [19]. The neurofibromin 1 (NF1) gene is considered one of the driver genes in melanomas, specifically in chronically sun-exposed or older subjects and in desmoplastic melanoma.…”

Secondary Resistant Mutations to Small Molecule Inhibitors in Cancer Cells

“…It has also been characterized as a dependence receptor which can function in the absence of a ligand to trigger apoptosis [359]. KIT signals through the PI3K-AKT-mTOR pathway to promote anti-apoptosis and through the RAS-RAF-MEK-MAPK pathway to activate proliferation ( Figure 3A) [360,361]. Activating c-KIT oncogenic mutations have been first identified in gastrointestinal and leukemia cancers [362][363][364] as well as a variety of other hematopoietic cancers [365,366].…”

Zebrafish Kit ligands cooperate with erythropoietin to promote erythroid cell expansion

“…Interestingly, there are two forms of KITLG occurring in vivo -transmembrane, important for the regulation of stem cells in their niches, and soluble, affecting more distant tissues 13,20 . Binding of KITLG to its receptor KIT, a member of receptor tyrosine kinase type-III family, leads to its autophosphorylation, further triggering various signaling cascades, including PI-3K, MAPK, SRC and JAK kinase pathways 20,21 .…”