• What is KIT?
  • KIT in Melanoma
  • KIT c.1676T>C (V559A)
  • 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/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

KIT c.1676T>C (V559A) Mutation in Melanoma

Properties
Location of mutation Juxtamembrane domain (exon 11)
Frequency of KIT mutations in all malignant melanomas
Frequency of KIT mutations in acral melanomas
Frequency of KIT mutations in mucosal melanomas
2–8% (Beadling et al. 2008; COSMIC; Curtin et al. 2006; Handolias et al. 2010; Willmore-Payne et al. 2005)
10–20% (Beadling et al. 2008; Curtin et al. 2006; Satzger et al. 2008; Torres-Cabala et al. 2009)
15–20% (Beadling et al. 2008; Curtin et al. 2006; Satzger et al. 2008; Torres-Cabala et al. 2009)
Frequency of V559A mutation among KIT-mutated malignant melanomas ~20%
Implications for Targeted Therapeutics
Response to nilotinib Confers increased sensitivitya
Response to imatinib Confers increased sensitivityb
Response to sunitinib Confers increased sensitivityc
Response to sorafenib Confers increased sensitivityd

 

The V559A mutation results in an amino acid substitution at position 559 in KIT, from a valine (V) to an alanine (A). This mutation occurs within the juxtamembrane domain (Figure 1). Mutant KIT proteins have increased kinase activity and transforming activity in vitro (Growney et al. 2005; Hirota et al. 1998; Hirota et al. 2001; Kitayama et al. 1995). KIT mutations are usually found in tumors with no driver mutations detected in NRAS, BRAF, and other genes.

 

a In a phase II clinical trial, 5 of 26 patients with melanoma harboring KIT mutations responded to nilotinib (Lebbe et al. 2014).

b Phase II studies have demonstrated clinical responses of KIT-mutated melanoma to imatinib (Carvajal et al. 2011; Hodi et al. 2008; Lutzky, Bauer, and Bastian 2008; Terheyden et al. 2010). In addition, the KIT V559A mutation was sensitive to imatinib in preclinical studies (Antonescu et al. 2007Beadling et al. 2008Curtin et al. 2006). In recent case reports, two patients with V559A-mutated melanoma showed a clinical benefit (CR, PR or SD) on imatinib (Terheyden et al. 2010). In a phase II trial of imatinib in 25 patients with mucosal melanoma, acral melanoma, and melanoma arising from chronic sun damage harboring KIT mutations or amplification, disease control rates were correlated positively with KIT mutations but not KIT amplification. Four patients with NRAS mutations did not show response to imatinib, suggesting that this is a mechanism of resistance (Hodi et al. 2013).

c A case report has demonstrated clinical reponse of a KIT mutated melanoma to sunitinib (Zhu et al. 2009). In addition, three out of four evaluable patients with KIT mutations (two with L576P and one with W557G) responded to sunitinib in a recent study (Minor et al. 2012). Responses of patients with KIT-mutated melanomas who were not given sunitinib were not reported (Minor et al. 2012​).

d A case has been reported of clinical response of a KIT V560D-mutated melanoma to sorafenib (Quintas-Cardama et al. 2008). ​

 

Reference Study Type / Phase Line of Treatment Treatment Agent Mutation Status # Patients in Study Response Rate PFS OS
Lebbe et al. 2014 Phase II 1st line or greater nilotinib KIT mutation and/or amplification 25 20%   68.3% at one year
KIT mutation only 20 25%    
KIT amplification only 2 0%    
KIT mutation and amplification 3 0%    
Hodi et al. 2013 Phase II 1st line or greater; no prior KIT inhibitor treatment imatinib KIT mutation and/or amplification 24 29% 3.7 (TTP) 12.5
KIT mutation only or KIT mutation and amplification 13 54%    
KIT amplification only 11 0%    
Guo et al. 2011 Phase II 1st line or greater imatinib KIT mutation and/or amplification 43 23% 3.5 months 51% at one year
KIT amplification 3 33%    
KIT exon 9 mutation 3 0%    
KIT exon 11 mutations 17 35%    
KIT exon 13 mutations 9 33%    
KIT exon 17 mutations 5 0%    
KIT exon 18 mutations 6 0%    
Multiple KIT aberrations 5 60%    
Carvajal et al. 2011 Phase II 1st line or greater​ imatinib KIT mutation and/or amplification 25 24% 12 weeks 46.3 weeks
KIT amplification (regardless of mutation) 15 27%    
KIT mutation (regardless of amplification) 21 29%    
KIT N463S mutation 1 0%    
KIT V559C mutation 1 0%    
KIT Y570H mutation 1 0%    
KIT L576P mutation 6 67%    
KIT K642E mutation 4 50%    
KIT I653T mutation 1 0%    
KIT V654A mutation 1 0%    
KIT D820Y mutation 1 0%    
KIT N822K mutation 1 0%    
KIT A829P mutation 1 0%    
KIT P838L mutation 1 0%    
KIT V852I mutation 1 0%    

NOTE: OS = overall survival; PFS = progression-free survival; TTP = time to progression.

KIT V559A



Figure 1.
Schematic of KIT V559A mutation. Domains of the KIT tyrosine kinase are shown. NOTE: JM = juxtamembrane domain; TM = transmembrane domain.

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 c.1676T>C (V559A) Mutation in Melanoma. My Cancer Genome https://www.padiracinnovation.org/content/disease/melanoma/kit/112/ (Updated June 16).

Last Updated: June 16, 2015

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