• What is KIT?
  • KIT in GIST
  • KIT Exon 11 Mutation
  • Clinical Trials


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 signal transducer and activator of transcription 3 (acute-phase response factor), or STAT3, pathway, all of which are involved in mediating pro-growth and pro-survival signals within the cell (Figure 1).

Mutant KIT has been implicated in the pathogenesis of several cancers including melanoma, acute leukemia, and gastrointestinal stromal tumor (GIST; Heinrich et al. 2003; Hirota et al. 1998).

The discovery of KIT mutations revolutionized the treatment of GISTs. The use of imatinib mesylate (Gleevec), 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 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 pathway. The letter "K" within the schema denotes the tyrosine kinase domain.

Related Pathways

Contributors: Christine M. Lovly, M.D., Ph.D., Jeff Sosman, M.D., William Pao, M.D., Ph.D. (through April 2014)

Suggested Citation: Lovly, C., J. Sosman, W. Pao. 2015. KIT. My Cancer Genome https://www.padiracinnovation.org/content/disease/gist/kit/?tab=0 (Updated December 7).

Last Updated: December 7, 2015


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. ​

Contributors: Robert G. Maki, M.D., Ph.D., FACP, Vicki Keedy, M.D., M.S.C.I.

Suggested Citation: Maki, R., V. Keedy. 2014. KIT in GIST. My Cancer Genome https://www.padiracinnovation.org/content/disease/gist/kit/ (Updated September 29).

Last Updated: September 29, 2014

KIT Exon 11 Mutation in GIST

Location of mutation Juxtamembrane domain
Frequency of KIT mutations in GIST ~85% (Heinrich et al. 2003)
Frequency of KIT exon 11 mutations in KIT-mutated GIST ~70% (Heinrich et al. 2003)
Implications for Targeted Therapeutics
Response to imatinib Confers increased sensitivity
Response to sunitinib Decreased sensitivity to second-line sunitinib;
Too few patients have been treated in the imatinib-naïve setting
Response to sorafenib Some evidence of activity (Kindler et al. 2011; Ryu et al. 2011)
Response to nilotinib Unknown at this time
Response to dasatinib Unknown at this time

Compared to patients with KIT exon 9 mutations and wild type GIST, patients with exon 11 mutations have a worse relapse free survival and overall survival; however, their tumors have the highest sensitivity to imatinib with a median duration of benefit of approximately 23 months. Patients with exon 11 mutations are less likely to respond to second-line sunitinib (5% RR; Heinrich et al. 2008).

Adjuvant imatinib significantly improves relapse free survival for patients with exon 11 mutated GIST, HR 4.85 (95% CI 1.49–15.76; Corless et al. 2010). There is a relapse free survival benefit of 3 years compared to 1 year of adjuvant imatinib for patients with exon 11 mutated GIST in the high-risk category (i.e., >5 cm, >5/50 HPF mitotic count), HR 0.35, p<0.001 (Joensuu et al. 2011), but it is not clear if there is a survival advantage to 3 years vs 1 year of imatinib (or observation); data are too immature to draw such conclusions at present.


Figure 1.
Schematic of KIT. Domains encoded by various exons are shown.​

Contributors: Robert G. Maki, M.D., Ph.D., FACP, Vicki Keedy, M.D., M.S.C.I.

Suggested Citation: Maki, R., V. Keedy. 2014. KIT Exon 11 Mutation in GIST. My Cancer Genome https://www.padiracinnovation.org/content/disease/gist/kit/47/ (Updated September 29).

Last Updated: September 29, 2014

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