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

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