ABSTRACT
Figure 9.1 Schematic structure of KIT and PDGFRA (adapted from [45]). In the mutated state, KIT is activated even in the absence of its ligand and its downstream effectors including the phosphatidyli-nositol 3-kinase (PI3K) and the mitogen-activated kinase (MAPK) pathways affect the cell cycle, translation, metabolism and apoptosis [41] and upon exposure to imatinib show rapid downregulation of these pathways (Fig. 9.2). Many studies have now evaluated clinical GIST samples and confirmed that up to 80% of GISTs harbor a KIT gene mutation (Fig. 9.1) [4, 9, 10, 13, 42-45]. Based on these initial screens, it was determined that the majority of mutations were found in a limited portion of the gene, i.e., exons 9, 11, 13, and 17. These exons encode for a small region of the extracellular domain (exon 9), the juxtamembrane domain (exon 11), and the split kinase domains, I and II (exons 13 and 17), respectively. In approximately two-third of GISTs, KIT mutations occur within exon 11 sequences. Mutations at this site release KIT from auto-inhibition and result in constitutive activation [13]. Generally mutations involving exon 11 are responsive to therapy with the tyrosine kinase inhibitor imatinib mesylate (discussed in Section 9.4.4.1). Varying types of mutations may occur. Some studies have shown deletions to characterize more adverse acting tumors than substitutions [46]. A small number of exon 11 mutations are internal tandem duplications and the corresponding
tumors tend to be gastric in location and have more favorable behavior [47, 48].
