KIT

C-kit is a gene encoding the receptor tyrosine kinase protein (also known as CD117) and was originally thought to be a homologue of the Feline sarcoma Viral Oncogene V-kit, involved in intracellular signaling (PMID: 2448137). C-kit belongs to class III of the RTK family and has hydrophobic transmembrane domains, extracellular ligand binding domains, and tyrosine kinase domains, expressing receptor tyrosine kinase (RTK) in a variety of cell types (PMID: 17855052). Stem cell factor (SCF) is the receptor of KIT (PMID: 10582338, PMID: 17855052), when KIT binds to SCF, it forms a dimer to activate tyrosine kinase activity, which then phosphorylates and activates several pathways including RAS-ERK, PI3K, MAPK and STAT. Thus, it plays an important role in hematopoiesis, stem cell maintenance, gametogenesis, melanin production and the migration and function of mast cell development (PMID: 10582338, PMID: 12134156). Mutations in KIT are associated with gastrointestinal stromal tumors (GIST), mastocytosis, acute myeloid leukemia (AML), and piebaldism (PMID: 1720553).

Currently, tyrosine kinase inhibitors are the main treatment options for c-KIT mutations. Imatinib is the main FDA-approved first-line treatment for metastatic and adjuvant prevention of adverse or recurrent GIST after surgical resection (PMID: 22089421, PMID: 15123710), which effectively inhibits the activity of KIT and PDGFR by competing for binding sites with ATP. Imatinib is highly sensitive to Exon11 mutations such as V560G and has strong efficacy in GIST and SM, but secondary mutations could affect the efficacy of imatinib. For example, the treatment of Exon9 mutation requires increased dose (PMID: 16624552), and it is resistant to SM and AML with mutations in Exon8 and Exon17 such as D861V, D419 and N822L (PMID: 15621779, PMID: 15650049). The second-generation inhibitor nilotinib, effectively inhibited the V560G mutant (PMID: 17363509). Sunitinib is a KIT receptor multikinase inhibitor approved by the FDA for the first-line treatment of renal cell carcinoma and pancreatic neuroendocrine tumors and for the second-line treatment of GIST (after imatinib treatment). Sunitinib is an effective inhibitor of KIT V599D and T760I dual mutants. The drug was initially developed as an antiangiogenic agent that inhibited KIT, PDGF and VEGFR as well as FLT3. Sunitinib is a potent inhibitor of nearly all KIT Exon9 and Exon 11 segment mutations (PMID: 16046538, PMID: 17367763). Dasatinib was originally developed as a BCR-ABL inhibitor and is a dual inhibitor of KIT and SRC kinase. Dasatinib is effective against the KIT D816V mutant. Dasatinib has been approved by the FDA for first- or second-line treatment of Ph + CML or second-line treatment of Ph + ALL (PMID: 16434489, PMID: 16436588). Regorafenib is a KIT multikinase inhibitor that is used to treat GIST following third-line therapy with sorafenib, imatinib and sunitinib (PMID: 21170960). Sorafenib is an FDA-approved KIT receptor multikinase inhibitor originally developed as a Raf protein serine/threonine kinase inhibitor for the first-line treatment of hepatocyte and renal cell carcinoma (PMID: 17699867). Midostaurin, originally developed as a PKC protein-serine/threonine kinase inhibitor, is FDA-approved for first-line mastocytosis and combination therapy for FLT mutated AML. Midostaurin was effective against D816V/Y mutation on KIT Exon 17 (PMID: 15790786, PMID: 17363509). Ponatinib is a KIT receptor multikinase inhibitor that has been approved for the treatment of ALL and CML in Ph+ patients. A recent clinical study showed that ponatinib has a much stronger inhibitory effect on Melanoma patients than imatinib (PMID: 31037149).