Table 1.
c-KIT Mutations and the Clinical Significance of Some TKIs in Different Types of Cancer
| Type of Tumor | Types of c-KIT Mutation | TKIs | Clinical Significance | Approval |
|---|---|---|---|---|
| Gastrointestinal stromal tumors (GISTs) | Gain-of-function mutation in exons 11, 9, 13, 14, and 17 | Imatinib mesylate | Binds to the ATP binding sites on CD117 and PDGFRA, resulting in signal transduction suppression | Approved by FDA in 2001 |
| Sunitinib | Effective for patients with exon 13/14 secondary c-kit mutations | Approved by FDA in 2006 | ||
| Regorafenib | Effective choice for patients with secondary exon 13/14 or exon 17/18 mutations | Approved by FDA in 2013 | ||
| Ripretinib | Blocks the two switch sites present in the juxtamembrane domain (exon 11) and in the activation loop (exons 17 and 18) | Approved by FDA in 2020 | ||
| Avapritinib | Effective for the activation loop mutants, which are encoded by exon 17 | Approved by FDA in 2020 | ||
| Pimitespib | HSP90 inhibitor28 | Approved in Japan in 2022 | ||
| Leukemias | Gain-of-function mutation in exons 8 and 17 | Imatinib mesylate | Used as a maintenance therapy after the completion of post-remission therapy29 | Approved by FDA in 2001 |
| Dasatinib | Effective in c-KIT-mutated CBF-AML30 | Approved by FDA for Ph+ CML | ||
| Radotinib | Anti-leukemic therapy for c-KIT-positive AML patients31 | Approved by FDA in 2012 | ||
| Pimitespib | HSP90 inhibitor32 | |||
| Melanoma | Loss-of-function mutations.20,33 Activation mutations in exons 11, 13, 9, and 1734–38 |
Imatinib, nilotinib, dasatinib sunitinib, sorafenib, masitinib39 | Research was conducted on the combination of TKIs with other therapeutic modalities40–43 | |
| Breast cancer (BC) | Loss-of-function mutations.22,44,45 Activation mutations in TNBC and adenoid cystic carcinoma46–53 | Lapatinib | Approved for HER2-positive BC, as it also targets EGFRs53,54 | Approved by FDA in 2007 |
| Nilotinib | A potent drug for TNBC treatment53 | |||
| Colorectal carcinoma (CRC) | Activation mutations in the consensus molecular subtype 4 (CMS4) subtype55 | Bufalin | Blocks the C-Kit/Slug signaling axis56 | Approved by Chinese FDA |
| Imatinib | Mitigates the aggressive behavior of CRC-CMS4, and induces genes responsible for CMS-switching57–60 | |||
| Renal cell carcinoma (RCC) | Activation mutations61–65 | Sorafenib, sunitinib, pazopanib, axitinib, cabozantinib, lenvatinib | Considered the standard of care in patients with advanced RCC66–69 | |
| Mastocytosis (MC) | Missense mutations affecting exons 17, 18, 11, 8, and 95,70–72 | Imatinib | Approved by US FDA for systemic MC73 | |
| Midostaurin | Multikinase/KIT inhibitor against D816V mutant MC74 | Approved by FDA, EMA, and AIFA7,75 | ||
| Avapritinib | Small molecule kinase inhibitor of the activation-loop mutations of c-KIT including KIT D816V74 | Approved by FDA and EMA74 | ||
| Ripretinib | Type II switch pocket control inhibitor of c-KIT exon 1776 | Under trial (NCT02571036)76 | ||
| Germ cell tumors (GCTs) | Activation mutations in exons 11, and 17 | Imatinib | Effective treatment for CNS germinoma patients who were resistant to standard chemotherapy and have c-Kit mutations77 | |
| Thyroid cancer (TC) | Downregulated in papillary, follicular, anaplastic, poorly differentiated, and differentiated TC78–82 | Motesanib, lenvatinib, sorafenib, pazopanib, sunitinib, cabozantinib, anlotinib83–90 | All are able to inhibit cell proliferation and angiogenesis by blocking VEGFR, FGFR, PDGFR, and c-Kit90 | Sorafenib and cabozantinib approved by FDA for TC |
| Lung cancer | c-KIT protein overexpression | Anlotinib | Approved by Chinese FDA91 | |
| Combined anti-c-Kit ADC plus anti-PD-L1 therapy92 | Could exhibit potential therapeutic efficacy against SCLC92 |
Abbreviations: ACC, Adenoid cyctic carcinoma; AIFA, Agenzia Italiana del Farmaco; AML, acute myeloid leukemia; CBF, core-binding factor; EGFR, epidermal growth factor receptor; EMA, European Medicines Agency; FDA, Food and Drug Administration; FGFR, fibroblast growth factor receptor; HSP90, heat shock protein-90; PDGFR, platelet-derived growth factor receptor; SCLC, small cell lung cancer; TKI, tyrosine kinase inhibitor; TNBC, triple-negative breast cancer; VEGFR, vascular endothelial growth factor receptor.