Targeting the molecular pathophysiology of gastrointestinal stromal tumors with imatinib. Mechanisms, successes, and challenges to rational drug development.

摘要: The development of imatinib as molecularly targeted therapy for GIST represents an important case study rational drug development. It is a paradigm how the molecular understanding cancer has resulted in new effective that targets critical pathway upon which cells were dependent: uncontrollably active KIT signaling pathway. Unresectable or metastatic GISTs have traditionally exhibited rapid and fatal clinical course, with no evidence benefit from any standard cytotoxic chemotherapy. identification activation factor pathogenesis led to search type therapeutic compound serve inhibitor interfere constitutive phosphorylation kinase cells. Clarification genetic pathophysiology role this disease, therefore, not only enabled improved diagnosis differentiation other mesenchymal neoplasms but also been key identifying strategies intervention. GIST, disease was previously untreatable available systemic therapy, imatinib, well-tolerated agent can inhibit dysregulated pathways GIST. Imatinib first (and currently only) patients unresectable induce objective responses stabilization provide majority treated drug. Other are beginning be explored, such use earlier course (e.g., adjuvant after definitive surgical resection early-stage disease). Integration signal transduction inhibitors into armamentarium therapeutics will undoubtedly continue based on