Our findings also explain, in part, the nonuniform response to KIT TKI treatment observed in KIT-mutant GIST patients and provide a rationale for testing an mTOR inhibitor in combination with a KIT TKI in KIT-mutant GIST patients. Several clinical or preclinical trials have been performed to test the efficacy of the combination of everolimus and imatinib in imatinib-resistant GISTs (44–46). Our studies demonstrate an enhanced synergistic effect of everolimus and imatinib in DEPDC5-deficient GISTs. These findings suggest that the combination therapy with mTOR and KIT inhibitors may work better in GISTs with DEPDC5 inactivation. DEPDC5 is an attractive therapeutic target in focal epilepsy (47, 48), as effects of DEPDC5 agonists would likely be anti-epileptogenic, and these DEPDC5 agonists warrant evaluation as potential therapeutic agents in oncology.