• What is KIT?
  • KIT in Thymic Carcinoma
  • KIT c.1727T>C (L576P)
  • 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/thymic-carcinoma/kit/?tab=0 (Updated December 7).

Last Updated: December 7, 2015

KIT in Thymic Carcinoma

KIT mutations are found in only 8.7% of thymic carcinomas (13/128 collectively analyzed) and are mutually exclusive with RAS mutations (Girard et al. 2009; Girard 2010). By contrast, KIT is overexpressed in 87% of thymic carcinomas by immunohistochemistry (IHC; Pan, Chen, and Chiang 2004; Henley, Cummings, and Loehrer 2004; Petrini et al. 2010). Given such a high frequency, KIT IHC positivity may be considered as a diagnostic marker for thymic carcinoma vs. thymoma or lung carcinoma in the setting of a mediastinal tumor (Henley, Cummings, and Loehrer 2004).

Thymic carcinoma-associated KIT mutations have been detected primarily in the juxtamembrane domain and the kinase domain. They can induce ligand-independent receptor dimerization, constitutive kinase activity, and transformation (Growney et al. 2005; Hirota et al. 1998; Hirota et al. 2001). The spectrum of mutations overlaps with those found in gastrointestinal stromal tumor (GIST).

The clinical relevance of KIT mutations is more limited in thymic carcinoma than in GIST, because 1) KIT mutations are far less frequent; 2) KIT expression does not correlate with the presence of KIT mutation; and 3) treatment-naϊve KIT-mutated tumors are not uniformly sensitive to imatinib. These findings may explain why a phase II trial with the KIT inhibitor, imatinib, in which patients were selected based upon KIT staining by immunohistochemistry and not upon KIT genotyping, was disappointing (Salter et al. 2008). However, multiple case reports have documented disease responses to KIT tyrosine kinase inhibitors in patients harboring KIT-mutated thymic carcinomas (Girard 2010).

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Contributors: Nicolas Girard, M.D.

Suggested Citation: Girard, N. 2015. KIT in Thymic Carcinoma. My Cancer Genome https://www.padiracinnovation.org/content/disease/thymic-carcinoma/kit/ (Updated March 6).

Last Updated: March 6, 2015

KIT c.1727T>C (L576P) Mutation in Thymic Carcinoma

Properties
Location of mutation Juxtamembrane domain (exon 11)
Frequency of KIT mutations in thymic carcinoma 8.7% (Girard 2010)
Frequency of L576P mutation among KIT-mutated thymic carcinomas 2 cases reported (Schirosi et al. 2012​Yoh et al. 2008)
Implications for Targeted Therapeutics
Response to imatinib (KIT inhibitor) May confer sensitivitya
Response to sunitinib (KIT inhibitor) May confer increased sensitivitya
Response to dasatinib (KIT inhibitor) May confer increased sensitivitya

The KIT L576P mutation occurs within the juxtamembrane domain (Figure 1). Mutant KIT proteins have increased kinase activity and transforming activity in vitro (Antonescu et al. 2007).

a A KIT-mutated case of thymic carcinoma reported in the literature harbored an L576P mutation in exon 11 (Yoh et al. 2008). No follow-up of the patient was reported regarding therapeutics with specific inhibitors. However, this mutation has also previously been described in GIST and melanoma. It has been biologically characterized as being sensitive to imatinib but even more sensitive to sunitinib and dasatinib (Antonescu et al. 2007).

KIT L576P



Figure 1.
Schematic of KIT L576P mutation. Domains of the KIT tyrosine kinase are shown. NOTE: JM = juxtamembrane domain; TM = transmembrane domain.

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Contributors: Nicolas Girard, M.D.

Suggested Citation: Girard, N. 2015. KIT c.1727T>C (L576P) Mutation in Thymic Carcinoma. My Cancer Genome https://www.padiracinnovation.org/content/disease/thymic-carcinoma/kit/96/ (Updated March 6).

Last Updated: March 6, 2015

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