Journal of surgical oncology
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Gastrointestinal stromal tumor (GIST), the most common sarcoma arising in the gastrointestinal tract, typically expresses the tyrosine-kinase receptor, C-KIT, and contains activating mutation in the c-kit or platelet-derived growth factor receptor (pdgfr) gene. Recently, development of small molecules that inhibit the kinase activity of mutant C-KIT and PDGFR proteins has radically changed treatment and prognosis of patients diagnosed with advanced GIST as this molecularly "targeted" therapy has demonstrated remarkable high-level of activity in this disease.
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Progression on first-line therapy with imatinib in gastrointestinal stromal tumors (GIST) is caused by either initial resistance or more often a secondary mutation in tyrosine kinases KIT or PDGFR. Therapies in development for imatinib-resistant GIST include agents that target KIT/PDGFR with greater potency or possess broader kinase inhibition profiles including VEGFR. To circumvent secondary mutations in KIT/PDGFR, inhibition of the downstream signaling in PI3K/Akt/mTOR pathway and enhanced degradation of KIT/PDGFR are also under investigation.