Memorial Sloan Kettering medical oncologists and sarcoma specialists William Tap and Ping Chi describe an investigational combination therapy for untreated advanced gastrointestinal stromal tumors (GIST). Imatinib has been used to treat these tumors and works by inhibiting an enzyme called tyrosine kinase, but in many patients the tumor develops resistance to this drug, and progresses. Memorial Sloan Kettering investigators have designed a study to assess the combination of imatinib with MEK162, an investigational drug that inhibits the MEK1/2 protein. Laboratory research findings indicate that targeting two proteins involved in GIST pathogenesis — ETV1 and mutant KIT — may be an effective first-line therapy for advanced GIST. Our trial is based on this research and may highlight a way to strengthen the effectiveness of imatinib against GIST by combining it with an MEK inhibitor.