• What is KIT?
  • KIT in GIST
  • KIT No Mutation Detected
  • 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

No Mutation Detected in KIT, PDGFRA and BRAF in GIST

Location of mutation N/A
Frequency of no mutation detected in KIT/PDGFRA/BRAF in GIST 12–15% (Heinrich et al. 2003)
Implications for Targeted Therapeutics
Response to imatinib Confers decreased sensitivity
Response to sunitinib Some evidence of activity
Response to sorafenib Some evidence of activity (Kindler et al. 2011)
Response to nilotinib Unknown at this time
Response to regorafenib Evidence of activity (Demetri et al. 2013)
Response to dasatinib Some evidence of activity (Schittenhelm et al. 2006; Trent et al. 2011)

GISTs with no detected mutations in KIT, PDGFRA, and BRAF were formerly referred to as wild type; more precisely, wild type refers to those GISTs that do not have mutations in KIT, PDGFRA, and BRAF. A significant proportion of GISTs without other mutations have mutations instead in genes encoding the protein succinate dehydrogenase (SDH), most commonly SDHB (Janeway et al. 2010​) or SDHA. Approximately half of people with no KIT, PDGFRA, and BRAF mutations detected in their metastatic GIST have stable disease for ≥ 6 months when treated with second line sunitinib (Heinrich et al. 2008). Furthermore, people who get worse despite imatinib and sunitinib for their metastatic GIST, regorafenib is useful, whether or not there are KIT, PDGFRA, and BRAF mutations (Demetri et al. 2013).

Of note, “no mutation detected” means that tumors were tested for one or more mutations in one or more genes and none of these specific mutations were detected. “No mutation detected” is sometimes referred to as “wild type.” However, these two terms do not refer to precisely the same thing. Strictly speaking, the mutation status should be qualified based on the testing method used. For example, if the testing only included amino acid V600 in BRAF and no mutation was detected, then the BRAF mutation status for that tumor would be "wild type at amino acid V600." Since we now know more about mutations in genes other than KIT, PDGFRA, and BRAF, the “wild type” terminology is out of date.

One year of adjuvant imatinib does not improve relapse free survival for people with GISTs that have no KIT, PDGFRA, and BRAF mutations, p=0.6 (Corless et al. 2010). For people with no KIT, PDGFRA, and BRAF mutations detected in GIST in the high-risk category (i.e., > 5 cm, > 5/50 HPF mitotic count), there may be some benefit of 3 years compared to 1 year of adjuvant imatinib; however, too few people were included to make a definitive recommendation, HR 0.41, p=0.1 (Joensuu et al. 2011). ​

Note that this page is cross-listed under BRAF no mutation detected and PDGFRA no mutation detected in GIST.


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

Suggested Citation: Maki, R., V. Keedy. 2014. No Mutation Detected in KIT, PDGFRA and BRAF in GIST. My Cancer Genome https://www.padiracinnovation.org/content/disease/gist/kit/56/ (Updated October 21).

Last Updated: October 21, 2014

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