New strategies for treating GIST when imatinib fails

Gastrointestinal stromal tumors (GISTs) are soft tissue sarcomas arising in the GI tract. Most GISTs have an activating mutation in KIT or PDGFR-alpha and respond to treatment with imatinib mesylate (Gleevec, Novartis), a small molecule tyrosine kinase inhibitor that blocks downstream signaling of the mutated kinase. Imatinib has dramatically improved survival in patients with unresectable or metastatic GIST; however, approximately 15 percent of patients do not respond to imatinib, and many others progress after an initial period of response or disease stabilization. New agents that target multiple kinases in GIST as well as downstream effector molecules are being developed and tested in clinical trials.