Mutation in K‐RAS (K‐RAS‐MT) plays important roles in both cancer progression and resistance to anti‐epidermal growth factor receptor (EGFR) therapy in gastrointestinal tumors. Insulin‐like growth factor‐1 receptor (IGF‐1R) signaling is required for carcinogenicity and progression of many tumors as well. We have previously shown successful therapy for gastrointestinal cancer cell lines bearing a K‐RAS mutation using an anti‐IGF‐1R monoclonal antibody. In this study, we sought to evaluate effects of forced K‐RAS‐MT expression on gastrointestinal cancer cell lines representing a possible second resistance mechanism for anti‐EGFR therapy and IGF‐1R‐targeted therapy for these transfectants. We made stable transfectants of K‐RAS‐MT in two gastrointestinal cancer cell lines, colorectal RKO and pancreatic BxPC‐3. We assessed the effect of forced expression of K‐RAS‐MT on proliferation, apoptosis, migration, and invasion in gastrointestinal cancer cells. Then we assessed anti‐tumor effects of dominant negative IGF‐1R (IGF‐1R/dn) and an IGF‐1R inhibitor, picropodophyllin, on the K‐RAS‐MT transfectants. Overexpression of K‐RAS‐MT in gastrointestinal cancer cell lines led to more aggressive phenotypes, with increased proliferation, decreased apoptosis, and increased motility and invasion. IGF‐1R blockade suppressed cell growth, colony formation, migration, and invasion, and up‐regulated chemotherapy‐induced apoptosis of gastrointestinal cancer cells, even when K‐RAS‐MT was over‐expressed. IGF‐1R blockade inhibited the Akt pathway more than the extracellular signal‐regulated kinase (ERK) pathway in the K‐RAS‐MT transfectants. IGF‐1R/dn, moreover, inhibited the growth of murine xenografts expressing K‐RAS‐MT. Thus, K‐RAS‐MT might be important for progressive phonotype observed in gastrointestinal cancers. IGF‐1R decoy is a candidate molecular therapeutic approach for gastrointestinal cancers even if K‐RAS is mutated. © 2016 Wiley Periodicals, Inc.