• What is KIT?
  • KIT in Melanoma
  • 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

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