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KIT mutation is the driver behind most gastrointestinal stromal tumours, and the reason imatinib turned a sarcoma with a median survival of about a year into a chronic disease.
KIT is the receptor tyrosine kinase for stem-cell factor, and activating mutations in it drive roughly 75 to 80 percent of gastrointestinal stromal tumours (GIST), with PDGFRA mutations accounting for about 10 percent more. Imatinib turned a sarcoma with a median survival of about a year into a chronic disease, and sunitinib, regorafenib, ripretinib and avapritinib (for PDGFRA D842V) form the sequence used as resistance mutations accumulate. KIT is also a target in systemic mastocytosis and is mutated in 2 to 3 percent of melanomas, enriched in acral and mucosal subtypes. Resistance arises through secondary KIT mutations that differ between patients, so later-line choice increasingly depends on the specific mutation. The plain version: KIT mutation is the driver behind most GIST, and blocking it is one of the clearest success stories of targeted therapy.
In plain words · KIT mutation is the driver behind most gastrointestinal stromal tumours, and the reason imatinib turned a sarcoma with a median survival of about a year into a chronic disease.
Backbone ribbon from PDB 2HYY. RCSB PDB 2HYY. The ribbon widens where the chain is folded into a regular pattern and narrows where it is a loose loop.
Backbone ribbon with the bound drug in ball-and-stick (pink carbons). The wireframe view adds the pocket residues within 5 Å as a thin cage.
KIT mutation is the driver behind most gastrointestinal stromal tumours, and the reason imatinib turned a sarcoma with a median survival of about a year into a chronic disease.
Stem-cell factor receptor tyrosine kinase.
14 products aim at KIT: small molecules. Kinases are switched on by binding ATP inside the cell, so most drugs are small molecules shaped to plug that ATP pocket.
Tumour-specific alteration: 1 of 1 label readouts filed under it measure a sequence variant (KIT D816V) absent from normal cells. HPA KIT: RNA tissue enhanced (breast 79 nTPM); blood lineage group enriched (granulocytes 16 nTPM, NK-cells 11 nTPM); high antibody staining in 2 normal tissues; highest cancer staining testis cancer (3 of 12 high). Distribution: 3 cancer families in the corpus carry a prevalence row, label threshold or catalogue link for it (Sarcomas (soft tissue, bone, GIST), Skin cancer (all types), Myeloid neoplasms); approvals of single-target medicines aimed at it also list Leukaemia, not counted; Open Targets associates it with 17 specific cancer types at or above 0.5 (gastrointestinal stromal tumor, cutaneous mastocytosis, acute myeloid leukemia, chronic myeloid leukemia, hepatocellular carcinoma, mastocytosis and more). (Rule 3 of scripts/fetch-target-specificity.ts.)
Sources: KIT D816V label threshold; Human Protein Atlas KIT tissue; Open Targets ENSG00000157404 associations
First described 1987. Earliest sequence paper UniProt cites for the protein: Yarden et al, EMBO J, 1987, "Human proto-oncogene c-kit: a new cell surface receptor tyrosine kinase for an unidentified ligand". Source.
What a pathology or genomic report can say about this target, each with the thresholds approvals use.
Cell lines and mouse models for this target →
Stem-cell factor receptor tyrosine kinase.
RNA: tissue enhanced (breast 79 nTPM), detected in many normal tissues. Blood: group enriched (granulocytes 16 nTPM, NK-cells 11 nTPM).
Medium: Breast, Colon, Fallopian tube, Lung, Ovary, Rectum, Testis.
RNA cancer enhanced: Kidney Chromophobe 144 pTPM.
Medium only: carcinoid, lung cancer.
HPA KIT tissue · HPA KIT pathology · HPA protein class: CD markers, FDA approved drug targets
Human Protein Atlas version 25.1, antibody staining at reliability approved, enhanced or supported; used under CC BY-SA 3.0. Staining counts are patients per level in the atlas cohort, not population prevalence.
| Cancer | Prevalence | Measure | Note | Source |
|---|---|---|---|---|
| Sarcomas | 75-80% | GIST KIT mutation | PDGFRA in ~10% | Wikipedia |
| Melanoma | 2-3% | KIT mutation (acral/mucosal enriched) | cBioPortal (TCGA) |
Approximate, population-level figures; the measure column says what was counted. Ranges show the midpoint as a bar.
AL2846 is an experimental small-molecule drug from Chia Tai Tianqing Pharmaceutical in phase 3 trials for thyroid cancer, aimed at MET and RET.
Anlotinib is one of the most used cancer pills in China, first approved for lung cancer after other treatments have failed and then for several rarer tumours.
Avapritinib is the first drug for GIST driven by the PDGFRA D842V mutation, which resists every other kinase inhibitor; it is also approved for systemic mastocytosis.
Bezuclastinib is an experimental small-molecule drug from Cogent Biosciences in phase 3 trials for gastrointestinal stromal tumour, aimed at KIT and MET.
Chiauranib is an experimental small-molecule drug from Chipscreen Biosciences in phase 3 trials for ovarian cancer, aimed at VEGF / VEGFR and KIT.
The drug that started the targeted therapy era in 2001, turning chronic myeloid leukaemia into a manageable condition with near-normal life expectancy.
An oral anti-angiogenic pill that matched sorafenib in liver cancer with higher response rates, and partners with pembrolizumab in kidney and endometrial cancer.
The first drug to improve survival in FLT3-mutated AML, added to standard chemotherapy: median survival went from about two years to more than six.
Nilotinib is a second-generation CML pill that produces deeper responses faster than imatinib, at the cost of cardiovascular and metabolic side effects.
Pazopanib is the only multi-kinase inhibitor approved for soft-tissue sarcoma (excluding fat-derived tumours), used after chemotherapy fails.
Pexidartinib is the first drug for tenosynovial giant cell tumour, a benign but destructive joint tumour; it is effective but has liver toxicity that requires a restricted programme.
A sorafenib successor that became the first second-line drug proven to prolong life in liver cancer (2017).
A fourth-line GIST drug that locks KIT in an off state regardless of which resistance mutation the tumour has acquired.
Sunitinib is an anti-angiogenic pill approved for pancreatic neuroendocrine tumours, kidney cancer and GIST.
Query for this target: (TITLE:"KIT" OR ABSTRACT:"KIT") AND (cancer OR tumor OR tumour OR oncology OR carcinoma OR lymphoma OR leukemia OR leukaemia OR myeloma OR sarcoma OR melanoma OR glioma). Results are unfiltered search hits about KIT, not a curated reading list.
Shares Midostaurin, Advanced systemic mastocytosis (aggressive SM, SM with an associated haematological neoplasm, mast cell leukaemia), Acute myeloid leukaemia (KEGG map), Systemic mastocytosis and the tags driver, kinase.
Shares AL2846, Regorafenib, Lenvatinib, Receptor tyrosine kinase activation and the tags driver, kinase.
Shares Cogent Biosciences, Anlotinib, Lenvatinib, PI3K / AKT / mTOR and the tags driver, kinase.
Shares Vaginal melanoma, Vulvar melanoma, Acral melanoma, Gastrointestinal stromal tumour (GIST) and the tags driver, kinase.
Shares Lemmon and Schlessinger 2010: cell signalling by receptor tyrosine kinases, PI3K / AKT / mTOR, Receptor tyrosine kinase activation, RAS / RAF / MEK / ERK (MAPK) and the tags driver, kinase.
Shares PI3K / AKT / mTOR, Receptor tyrosine kinase activation, RAS / RAF / MEK / ERK (MAPK) and the tags driver, kinase.
Shares Cogent Biosciences, PI3K / AKT / mTOR, Receptor tyrosine kinase activation, Small-molecule kinase inhibitors and the tags driver, kinase.
Shares Lemmon and Schlessinger 2010: cell signalling by receptor tyrosine kinases, PI3K / AKT / mTOR, Receptor tyrosine kinase activation, RAS / RAF / MEK / ERK (MAPK) and the tags driver, kinase.