Gastrointestinal stromal tumors: a paradigm for therapeutic options in solid organ tumors

Although a relatively rare malignancy with a national incidence of 3500-4000 annually, Gastrointestinal Stromal Tumor (GIST) is of significance in the realm of clinical and pharmacological research. GIST exhibits remarkable uniformity in its pathogenesis and ultrastructure as 95% of cases are linked to constitutive activation and overexpression of a membrane tyrosine kinase, c-KIT (CD117). Although previously refractory to any course of action but surgery, GIST heralded a triumph in targeted cancer therapy when administration of a specific first-generation tyrosine-kinase inhibitor Imatinib mesylate (STI571) was shown to inhibit c-Kit and demonstrated a significant increase in patient survival. Over the subsequent decade, GIST has become a paradigm for the potency of Imatinib in adjuvant or neoadjuvant therapy, showcasing the clinical relevance and rapidity of translational research in the field of targeted molecular therapy. Subsequent to demonstrating the efficacy of Imatinib as a therapeutic agent, GIST has also exposed the limitations of current targeted therapies. Within two years, 50% of GISTs develop secondary mutations that allow resistance to Imatinib. However, extensive research regarding both primary and secondary c-KIT mutations has illuminated the mechanisms of Imatinib resistance and has the potential to ameliorate this therapeutic setback. Current research to this end lies in two primary directions: the development of tyrosine kinase inhibitors (some of which also inhibit other oncogenic agents such as PDGFR, bcr-abl, and VEGF) that are either generally more potent than Imatinib or less susceptible to specific mechanisms of resistance; and drugs that target the downstream effectors of the mutant c-KIT kinase, including PKC and mTOR. This paper will systematically review current research on second-generation targeted molecular therapy in the treatment of GIST, and expand upon its value as a model for treatment of other solid organ tumors.