Although their overall incidence is uncommon, gastrointestinal stromal
tumors (GIST) are the most frequently encountered mesenchymal
tumors of the GI tract. Their pathology has been recently defined by
the presence of KIT (transmembrane receptor tyrosine kinase). The
majority of GISTs have c-kit gain-of-function mutations mainly in exon
11 (highly conserved juxtamembrane region) that eventuates in constitutive
activation of KIT, promoting proliferation and antiapoptotic signaling.
Imatinib mesylate (Gleevec) is a specific inhibitor of KIT kinase
activation, and in phase II clinical trials has proven to be remarkably
efficacious in heavily pretreated GIST patients with advanced disease.
The molecular and genomic determinants of response/resistance
patterns are the subject of ongoing studies, and adjuvant studies are
also under way. The initial evaluations of imatinib provide proof of
concept for the hypothesis-driven design of selective molecularly targeted
therapies for solid tumor malignancies.