KIT (also called CD117), is a receptor tyrosine kinase (RTK) expressed on a wide variety of cell types. The ligand for KIT is stem cell factor (SCF). The binding of SCF to the extracellular domain of KIT induces receptor dimerization and activation of downstream signaling pathways, including the PI3K-AKT-mTOR pathway, the RAS-RAF-MEK-ERK pathway, and the STAT3 (Signal Transducer and Activator of Transcription 3) pathway, all of which are involved in mediating pro-growth and pro-survival signals within the cell (Figure 1).
The discovery of KIT mutations revolutionized the treatment of GISTs. The use of Imatinib mesylate (Gleevec, Novartis, Basel), an oral KIT inhibitor leads to rapid, substantial, and durable tumor responses (Demetri et al. 2002). Not all KIT mutations are associated with equal sensitivity to imatinib (Heinrich et al. 2008); some are more sensitive to second-generation KIT inhibitors.
Figure 1. Schematic of KIT signaling pathways. The binding of the ligand, stem cell factor (SCF), to the KIT receptor tyrosine kinase results in activation of the MAPK signaling pathway (RAS-RAF-MEK-ERK), the PI3K pathway (PI3K-AKT-mTOR), and the STAT3 (Signal Transducer and Activator of Transcription 3) pathway. The letter "K" within the schema denotes the tyrosine kinase domain.
Last Updated: June 1, 2012
KIT is mutated in ~85% of GIST (Heinrich et al. 2003). The vast majority of KIT mutations are found in exon 11 (juxtamembrane domain; ~70%), exon 9 (extracellular dimerization motif; 10–15%), exon 13 (tyrosine kinase 1 (TK1) domain; 1–3%), and exon 17 (tyrosine kinase 2 [TK2] domain and activation loop; 1–3%) (Heinrich et al. 2003). Secondary KIT mutations in exons 13, 14, 17, and 18 are commonly identified in post-imatinib biopsy specimens, after patients have developed acquired resistance.
Last Updated: June 1, 2012
|Location of mutation||Tyrosine kinase 1 (TK1) domain/ATP binding pocket|
|Frequency of KIT mutations in GIST||~85% (Heinrich et al. 2003)|
|Frequency of KIT exon 13 mutations in KIT-mutated GIST||1–3% (Heinrich et al. 2003)|
|Implications for Targeted Therapeutics|
|Response to imatinib||Confers sensitivity as a primary mutation;
Confers resistance as a secondary mutation
|Response to sunitinib||Sensitive in in vitro studies;
Too few patients in imatinib naïve or second-line settings to determine
|Response to sorafenib||Unknown at this time|
|Response to nilotinib||Unknown at this time|
|Response to dasatinib||Unknown at this time|
Although only a limited number of patients with primary KIT exon 13 mutations have been included in clinical trials with imatinib, clinical benefit appears to be similar to that of patients with exon 11 mutations (Heinrich et al. 2008).
In vitro studies suggest that sunitinib inhibits KIT double mutants harboring exon 13 mutations while imatinib does not. Too few patients have been included in clinical trials to have an accurate understanding of their response to treatment; however, small series suggest sunitinib may provide some benefit over imatinib in this setting (Heinrich et al. 2008).
Figure 1. Schematic of KIT. Domains encoded by various exons are shown.
Last Updated: November 30, 2012
Great effort was made to include all clinical trials relevant for this mutation. However, the completeness of this information cannot be guaranteed.
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