Activating mutations in c-KIT and PDGFRα are exclusively found in gastrointestinal stromal tumors and not in other tumors overexpressing these imatinib mesylate target genes

Previous studies have shown that Imatinib mesylate ( Gleevec), a selective tyrosine kinase inhibitor of c-KIT and platelet-derived growth factor receptors ( PDGFR), is highly effective in c-KIT/CD117-positive gastrointestinal stromal tumors ( GIST), especially in those having activating mutations in c-kit exon 11. In addition, gain-of-function mutations in the juxtamembrane domain ( exon 12) and the kinase activation loop ( exon 18) of PDGFR alpha were found in GISTs. Importantly, the presence and type of these mutually exclusive c-KIT or PDGFR alpha mutations were found to be associated with the response to imatinib. Here, we examined the prevalence of c-kit exon 11 and PDGFR alpha exons 12 and 18 mutations in other tumor types known to express these tyrosine kinase receptors in order to explore which other cancer types may potentially benefit from imatinib treatment. We determined the mutational status of these commonly mutated exons by direct sequencing in 11 different tumor types ( in total: 215 unrelated cases), including GIST, chordoma, and various distinct tumors of lung, brain and its coverings, and skin cancer. Of the 579 exons examined ( 211 c-kit exon 11, 192 PDGFR alpha exon 12, 142 PDGFR alpha exon18, 17 PDGFR beta exon 12 and 17 PDGFR beta exon 18), only 12 ( all GIST) harbored mutations ( 10 c-kit exon 11 and 2 PDGFR alpha exon18). From these data we conclude that activating c-KIT and PDGFR mutations are sporadic in human cancers known to overexpress these tyrosine kinase receptor genes and suggest that, except in GIST, this overexpression is not correlated with activating mutations. The latter may imply that these wild-type c-KIT and PDGFR tumor types will probably not benefit from imatinib treatment.