Imatinib Mesylate: A Molecularly Targeted Therapy for Gastrointestinal Stromal Tumors

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. Gastrointestinal stromal tumors (GISTs) are the most commonly recognized mesenchymal tumors of the GI tract. Their true incidence is approximately 10 to 20 cases per 1 million, and yet, their defining characteristics and biology have remained largely obscured until recently.[1,2] Beginning with histogenetic findings by Mazur and Clark in 1983[3] and culminating with the discovery of the obligatory presence of dysregulated KIT protein, a much clearer definition of the pathobiology of this clinical entity has emerged. The characterization of the molecular basis of this solid tumor has serendipitously coincided with the development of a small-molecule-specific targeted therapy and has provided a platform of discovery for rationally based hypothesis-driven clinical research. This review will outline the role of molecularly targeted therapies in the treatment of previously unresponsive solid tumors and will further elucidate how this bench-tobedside paradigm may provide a window into the future of cancer management. Gastrointestinal Stromal Tumors These unique stromal tumors of the GI tract have, in the past, been notably classified as spindle-cell nonepithelial smooth muscle tumors and were often grouped with leiomyosarcoma. However, careful examination by immunohistochemical (IHC) and ultrastructural analysis indicated that GISTs were distinct from other smooth muscle tumors and can have both myogenic and neurogenic features. This distinction was further elaborated by their similarity to the interstitial cells of Cajal (ICC), and it is now recognized that GIST cells and ICC cells are derived from a common progenitor or that perhaps the GIST cell is the neoplastic counterpart of the ICC cell.[4-6] By consensus, it was recently established that GISTs constitute a separate clinical entity and that they are generally identified by the IHC expression of CD117, the antigen to a specific transmembrane epitope of KIT.[7] Equally paramount in understanding the pathobiology of GISTs