• What is KIT?
  • KIT in Melanoma
  • KIT Other
  • 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/melanoma/kit/?tab=0 (Updated December 7).

Last Updated: December 7, 2015

KIT in Melanoma

Somatic mutations in KIT have been found in 2–8% (Beadling et al. 2008; COSMIC; Curtin et al. 2006; Handolias et al. 2010; Willmore-Payne et al. 2005) of all malignant melanoma. KIT mutations may be found in all melanoma subtypes but are the most common in acral melanomas (10–20%) and mucosal melanomas (15–20%; Beadling et al. 2008; Curtin et al. 2006; Satzger et al. 2008; Torres-Cabala et al. 2009). Among mucosal melanomas, KIT mutations are more common in anorectal and vulvo-vaginal primaries (15–25%) than in sinonasal/oropharyngeal tumors (~7%).

Somatic point mutations in melanoma tumor specimens have been detected predominantly in the juxtamembrane domain but also in the kinase domain of KIT. They can induce ligand-independent receptor dimerization, constitutive kinase activity, and transformation (Growney et al. 2005; Hirota et al. 1998; Hirota et al. 2001; Kitayama et al. 1995). The spectrum of mutations overlaps with those found in gastrointestinal stromal tumor (GIST).

An increasing number of case reports, retrospective studies, and phase II clinical trials have demonstrated clinical responses of KIT mutated melanoma to imatinib (Carvajal et al. 2011; Guo et al. 2011; Hodi et al. 2013), sunitinib (Minor et al. 2012​; Zhu et al. 2009), sorafenib (Quintas-Cardama et al. 2008), and nilotinib (Lebbe et al. 2014). In one case study, a patient with melanoma harboring a KIT L576P mutation demonstrated a response to everolimus after acquiring resistance to imatinib (Si et al. 2012).

In the majority of cases, KIT mutations are non-overlapping with other oncogenic mutations found in melanoma (e.g., NRAS mutations, BRAF mutations, etc.; Beadling et al. 2008). In addition, in rare cases the KIT genotype of a primary lesion may differ from its metastases (Terheyden et al. 2010).


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

Suggested Citation: Lovly, C., W. Pao, J. Sosman. 2015. KIT in Melanoma. My Cancer Genome https://www.padiracinnovation.org/content/disease/melanoma/kit/ (Updated June 18).

Last Updated: June 18, 2015

Other KIT mutations in Melanoma

Exon Mutation Preclinical Drug Sensitivity Reported Clinical Response(s)
Imatinib Sunitinib Sorafenib
9 A502–Y503insFA c.1507_1508insTTGCCT        
9 F504L c.1510T>C        
11 K550N   Sensitive Sensitive Sensitive  
11 Y553N   Sensitive Sensitive Sensitive  
11 Del 554–558   Sensitive Sensitive Sensitive  
11 Del 554–559   Sensitive Sensitive Sensitive  
11 556 ins L   Sensitive Sensitive Sensitive  
11 K558N   Sensitive Sensitive Sensitive  
11 V559G Sensitive Sensitive Sensitive  
11 Del V559   Sensitive Sensitive Sensitive  
11 V560A Sensitive Sensitive Sensitive Sorafenib: PR in 1 pt with V560A (Quintas-Cardama et al. 2008)
11 V560D c.1727T>C (V560D) Sensitive Sensitive Sensitive
11 V560G Sensitive Sensitive Sensitive
11 G565V          
11 Del 566–572   Sensitive Sensitive Sensitive  
11 Del 566–574 Sensitive Sensitive Sensitive  
11 N566D          
11 V569G          
11 575 ins PE   Sensitive Sensitive Sensitive  
11 Del 579   Sensitive Sensitive Sensitive  
11 E583_E589dupPYDHKWE Sensitive Sensitive Sensitive Imatinib: PR in 1 pt (Hodi et al. 2008)
13 R634W          
13 V654A   Resistant Sensitive    
13 N655          
13 N655S          
17 D816V Resistant Resistant Resistant
17 D820V   Intermediate   Sensitive  
17 D820Y   Intermediate   Sensitive Imatinib: PD in 1 pt (Carvajal et al. 2011); Sorafenib: PR in 1 pt (Handolias et al. 2010)
17 N822I   Intermediate   Sensitive  
17 N822Y   Intermediate   Sensitive  
17 N822K   Intermediate   Sensitive Imatinib: PD in 1 pt (Carvajal et al. 2011)
17 Y823D   Intermediate      
18 A829P   Resistant Resistant    
18 I841V          
18 S864F          
​NOTE: PD = progressive disease; PR = partial response.

Contributors: Christopher L. Corless, M.D., Ph.D. (through July 2013)

Suggested Citation: Corless, C. 2014. Other KIT mutations in Melanoma. My Cancer Genome https://www.padiracinnovation.org/content/disease/melanoma/kit/132/ (Updated October 22).

Last Updated: October 22, 2014

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