Given a broader knowledge of the mutational status and expression levels of c-Kit in IM-sensitive and resistant GIST patients, targeting c-Kit plus HER1 (IM or amuvatinib plus erlotinib or afatinib) or c-Kit plus c-Met/AXL (IM plus amuvatinib) with novel combinations of RTK inhibitors abrogates IM resistance in GIST. This evidence concerns the gene EGFR and gastrointestinal stromal tumor.