Targeting c-kit mutations in solid tumors: scientific rationale and novel therapeutic options.
Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of the gastrointestinal tract. These tumors span a wide clinical spectrum from benign to malignant and have long been recognized for their nearly absolute resistance to chemotherapy and radiation treatment. Surgery is the primary treatment modality for GISTs, but GISTs represent an incurable malignancy for patients with metastatic or unresectable disease. Thus, novel approaches to the treatment of GISTs were desperately needed. Gastrointestinal stromal tumors are characterized by expression of the transmembrane receptor tyrosine kinase KIT, which is defined by the CD117 antigen and is the product of the c-kit proto-oncogene. Activating or gain-of-function mutations in the c-kit gene have been identified in the majority of GIST cases. The resulting constitutive KIT tyrosine kinase activity was hypothesized to provide growth and survival signals to GIST cells and to be crucial to the pathogenesis of the disease. This hypothesis became testable with the identification of the signal transduction inhibitor imatinib mesylate (formerly STI571, [Gleevec]; Novartis Pharmaceuticals Corp, East Hanover, NJ), which blocks the tyrosine kinase activity of KIT as well as the kinase activity of the normal c-abl gene product, the oncogenic Bcr-Abl chimeric fusion protein of chronic myeloid leukemia, and the platelet-derived growth factor receptor. Preclinical experiments showed rapid inhibition of ligand-independent KIT phosphorylation, decreased cellular proliferation, and induction of apoptosis after exposure of GIST cells to imatinib mesylate in vitro. These results provided the rationale to move forward with clinical testing of imatinib mesylate as an anticancer therapy for GIST. In early 2000, a dramatic clinical and radiographic response to imatinib mesylate was shown in a single patient with advanced, chemotherapy-resistant GIST. The powerful scientific rationale for this proof-of-concept study, together with the durable and significant response observed in this first GIST patient treated with imatinib mesylate, have provided the driving force for rapid clinical development of this targeted therapy in this solid tumor indication.
Demetri
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Department of Adult Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA.
D000970:Antineoplastic Agents / Q000627:therapeutic use*; D001549:Benzamides; D002986:Clinical Trials as Topic; D004353:Drug Evaluation, Preclinical; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D005770:Gastrointestinal Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D006801:Humans; D000068877:Imatinib Mesylate; D008648:Mesoderm; D009154:Mutation; D009362:Neoplasm Metastasis; D010879:Piperazines / Q000627:therapeutic use*; D011379:Prognosis; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D000090063:Proto-Oncogene Mas; D019009:Proto-Oncogene Proteins c-kit / Q000235:genetics*; D011743:Pyrimidines / Q000627:therapeutic use*
D000970:Antineoplastic Agents; D001549:Benzamides; D004791:Enzyme Inhibitors; C000715470:MAS1 protein, human; D010879:Piperazines; D000090063:Proto-Oncogene Mas; D011743:Pyrimidines; D000068877:Imatinib Mesylate; D011505:Protein-Tyrosine Kinases; D019009:Proto-Oncogene Proteins c-kit