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 STAT3 (Signal Transducer and Activator of Transcription 3) 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, Novartis, Basel), 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 the ligand, stem cell factor (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 (Signal Transducer and Activator of Transcription 3) pathway. The letter "K" within the schema denotes the tyrosine kinase domain.
Last Updated: June 1, 2012
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). 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 mutant 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 mutant thymic carcinomas (Girard 2010).
Last Updated: December 17, 2012
KIT-Associated Thymic Carcinoma Clinical Trials
Great effort was made to include all clinical trials relevant for this mutation. However, the completeness of this information cannot be guaranteed.
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