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.

Keywords: c-Kit; cancer; cancer therapy; oncogene.

Figure 1

KIT cDNA and protein structure in different cancers and their respective mutations. Abbreviations: cDNA, complementary DNA; AML, acute myeloid leukemia; GIST, gastrointestinal stromal tumor.

Figure 2

Signal transducer and activator of transcription tyrosine kinase domain c-Kit in normal cell. Notes: Ras/Erk pathway directs to activate of the proliferation genes. PI3K pathway involves in antiapoptosis gene activation which results in cell survival. JAK/STAT pathway is associated in cell proliferation.

Figure 3

Signal transducer and activator of transcription tyrosine kinase domain c-Kit in cancer cell. Notes: The Ras-Erk pathway, PI3K/AKT pathway, and Src-signaling pathway have been demonstrated in this schematic picture. Although each of the signaling pathways goes through different ways and has different effects on cell function, the result of all of three pathways is inhibition of the cell apoptosis, resulting in tumorogenesis in different ways, such as inducing of cell proliferation, growth progression, or migration. Moreover, the mechanisms of c-Kit inhibitor drugs have been shown. Each group of c-Kit inhibitor drugs block different targets, which have been highlighted in red.