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.
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
Suggested Citation: Lovly, C., J. Sosman, W. Pao. 2015. KIT. My Cancer
(Updated December 7).
Last Updated: December 7, 2015
KIT in GIST
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.
Suggested Citation: Maki, R., V. Keedy. 2014. KIT in GIST. My Cancer
Genome https://www.padiracinnovation.org/content/disease/gist/kit/ (Updated
Last Updated: September 29, 2014
No Mutation Detected in KIT, PDGFRA and BRAF in GIST
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
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
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
Last Updated: October 21, 2014
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