Identification and treatment of chemoresistant inoperable or metastatic GIST: experience with the selective tyrosine kinase inhibitor imatinib mesylate (ST1571)

Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal neoplasms of the gastrointestinal tract. The concept of GIST and the definition of GIST pathology have evolved greatly over the past 5 years. GIST has been shown to share immunohistochemical, ultrastructural and histogenic similarities with the interstitial cells of Cajal. Both GIST and the interstitial cells of Cajal express KIT, the receptor tyrosine kinase that is the protein product of the c-kit proto-oncogene. KIT is universally phosphorylated in GISTs. Sequencing of c-kit complementary DNA from human GIST cells has demonstrated a high frequency of mutations that lead to constitutive activation of the KIT tyrosine kinase in the absence of stimulation by its physiologic ligand (stem cell factor). This, in turn, causes uncontrolled stimulation of downstream signaling cascades with aberrant cellular proliferation and resistance to apoptosis. Historically, malignant GIST has been highly refractory to conventional cytotoxic therapy. Signal transduction inhibition as cancer therapy was first tested successfully with imatinib mesylate (formerly known as STI571), a selective small-molecule tyrosine kinase inhibitor, with the initial target being blockade of Bcr-Abl, the oncogene with tyrosine kinase activity responsible for the pathogenesis of chronic myelogenous leukemia (CML). Imatinib was subsequently shown to block activity of the KIT tyrosine kinase as well, and in laboratory studies this led to apoptotic death of GIST cells. The first GIST patient to receive imatinib exhibited dramatic benefit despite far-advanced metastatic disease that was previously refractory to all chemotherapy. Subsequently, multicenter clinical trials have been performed to assess the safety, efficacy and biologic activity of imatinib in patients with advanced GIST. The results from these studies have established imatinib as an effective new therapeutic alternative for the majority of patients with advanced GIST, a solid tumor for which no prior chemotherapy has ever shown antitumor efficacy. This work provides proof of concept to the hypothesis that selective inhibition of aberrant signal transduction can provide important anticancer activity, if the proper signaling pathways are identified and blocked. (C) 2002,Elsevier Science Ltd. All rights reserved.