• What is KIT?
  • KIT in GIST
  • KIT Exon 9 Mutation
  • Clinical Trials

KIT

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.

kit-signaling.png

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 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. ​

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 9 Mutation in GIST

Properties
Location of mutation Extracellular dimerization motif
Frequency of KIT mutations in GIST ~85% (Heinrich et al. 2003)
Frequency of KIT exon 9 mutations in KIT-mutated GIST 10–15% (Heinrich et al. 2003)
Implications for Targeted Therapeutics
Response to imatinib Confers intermediate sensitivity;
Higher doses of imatinib (up to 800 mg total daily dose) may be more effective in metastatic disease than 400 mg oral daily
Response to sunitinib Confers increased sensitivity
Response to sorafenib Some evidence of activity (Ryu et al. 2011)
Response to nilotinib Unknown at this time
Response to dasatinib Unknown at this time

Compared to patients with KIT exon 11 mutations (Figure 1), patients with exon 9 mutations have a better relapse free survival and overall survival; however, their tumors show intermediate sensitivity to imatinib (Heinrich et al. 2008). Median duration of benefit from imatinib is approximately 7–12 months compared to 23 months for patients with exon 11 mutations.

Patients with exon 9 mutations are more likely to respond to second line sunitinib than patients with other KIT/PDGFRA mutations. A pooled-analysis of two studies comparing imatinib 400mg to imatinib 800mg showed an improved progression-free survival, but not overall survival, in patients with exon 9 mutated GIST (Van Glabbeke et al. 2007)

The effect of adjuvant imatinib on relapse-free survival for patients with exon 9 mutations is less than that for patients with exon 11 mutations; however, the number of patients is too small to make a definitive recommendation against adjuvant imatinib for these patients, p=0.8 (Corless et al. 2010). Conversely, there may be some benefit of 3 years compared to 1 year of adjuvant imatinib for patients with exon 9 mutated GIST in the high-risk category (i.e., >5 cm, > 5/50 HPF mitotic count); however, data are immature from this study and too few patients were included to make a definitive recommendation, HR 0.61, p=0.3 (Joensuu et al. 2011).

gist-kit.png

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

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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 9 Mutation in GIST. My Cancer Genome https://www.padiracinnovation.org/content/disease/gist/kit/46/ (Updated September 29).

Last Updated: September 29, 2014

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