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 Melanoma
Somatic mutations in KIT have been found in 2–8%
(Beadling et al. 2008;
Curtin et al. 2006; Handolias et al.
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.
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.
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).
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>A (V559D) Mutation in Melanoma
The V559D mutation results in an amino acid substitution at position 559 in KIT,
from a valine (V) to an aspartic acid (D). 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 V559D mutation was sensitive to imatinib
in preclinical studies (Antonescu
et al. 2007; Beadling
et al. 2008; Curtin
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.
d A case has been reported of clinical response of a KIT V560D-mutated
melanoma to sorafenib (Quintas-Cardama
et al. 2008).
NOTE: OS = overall survival; PFS = progression-free survival; TTP = time to progression.
Figure 1. Schematic of KIT V559D mutation.
Domains of the KIT tyrosine kinase are shown.
NOTE: JM = juxtamembrane domain; TM = transmembrane domain.
Suggested Citation: Lovly, C., W. Pao, J. Sosman. 2015. KIT c.1676T>A (V559D)
Mutation in Melanoma. My Cancer
(Updated June 16).
Last Updated: June 16, 2015
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