Meantime, additional studies found that interstitial cells of Cajal express KIT and are developmentally dependent on stem cell factor which is regulated through the KIT click here kinase (17,18). However, the following critical issues were not resolved: the exact origin

of GIST, the best way to diagnose GIST, and differentiation of benign from malignant GIST. As the developments in studies of GISTs, describing gain-of-function Inhibitors,research,lifescience,medical mutations and consequently, constitutive activation of KIT receptors in several human tumor cell lines was reported in the mid-1990s (19,20). Finally in 1998, Hirota and colleagues (21) discovered a specific mutation in the intracellular domain of the c-KIT protooncogene Inhibitors,research,lifescience,medical in GISTs as well as a near-universal expression of KIT protein in GISTs by immunohistochemistry. In the same year, Kindblom and colleagues (22)

corroborated findings from Hirota and colleagues by showing the immunoreactivity for KIT in 78 of 78 GISTs studied and GISTs Inhibitors,research,lifescience,medical shared striking ultrastructural and immunophenotypic similarities with interstitial cells of Cajal. Both studies supported the hypothesis that GIST may indeed derive from stem cells that differentiated toward interstitial Cajal phenotype and confirmed KIT as a diagnostic tool for GIST (23). The KIT mutation implied a gain-of function linked to the activation of the kinase even in the absence of the

binding of the ligand. The identification of the KIT mutation was a major breakthrough in the biology of GIST and overall, Inhibitors,research,lifescience,medical in cancer biology. The identification of the biologic driver, activating mutations in KIT provided a therapeutic target for the treatment of GIST. One patient with Inhibitors,research,lifescience,medical metastatic GIST refractory to multiple types of therapies was treated with STI-571 (Imatinib mesylate- Gleevec; Novartis, Basel, Switzerland), which is a small molecule tryosine kinase inhibitor (TKI) with potent activity against the transmembrane receptor KIT, ABL kinase and chimeric BCR-ABL fusion oncoprotein product Thalidomide of chronic myeloid leukemia. The treatment yielded an early, rapid, and sustained response (24) with supportive preclinical data (25,26). This case provided proof of principle that inhibition of KIT by drug therapy was associated with improvement in the disease and brought phenomenal growth in the understanding of GIST biology and therapeutics. Imatinib occupies the ATP binding pocket of KIT, thereby preventing substrate phosphorylation, downstream signaling, and thereby inhibiting cell proliferation and survival (23).