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drug resistant cancers Clinical and experimental evidence suggests strong potential for IGF-1-R antagonists to overcome resistance to anti-cancer chemotherapy drugs ( Also sustaining this hypothesis, other authors observed that modulation of IGF-1R-associated genes promoted regulatory clustering as well as stemness and chemoresistance in cells from colorectal cancer patients and mouse models, and was facilitated by a master transcriptional regulator responsive to ribosomal dysfunction, PR domain zinc finger protein 1 (PRDM1) ( in vitro and in vivo ( Interestingly, in a recent study using resistant colon cancer stem-like cells and mouse models, combination therapy of regorafenib with two antagonists of IGF-1-R, namely aspirin and the selective dual insulin receptor and IGF-1R kinase inhibitor linsitinib (OSI-906), abrogated tumor resistance to regorafenib and restored the drug’s ability to induce apoptosis in colon cancer stem-like cells and disease activity index ( 6 Challenges for clinical use of IGF-1R-silencing agents 6.1 Toxicity of IGF-1R antagonists Clinical trials of a large number IGF-1/2, IGF-1R, IRS-1, PI3K and mTOR antagonists have been abandoned due to limited anti-cancer activity, or to the toxicity of these agents ( Various study on IGF-1R, IGF-1 and IGF-2 expressions reported findings usable for useful patient stratification in future trials with inhibitors of the IGF-1R signaling pathway, to sort out those that may benefit the most from anti-IGF-1R therapies, limiting exposure of other patients to these agents ( 6.2 Need for IGF-1R targeting agents with higher specificity The drug candidates targeting IGF-1R signaling that are under clinical trial investigation include: IGF ligand inhibitors, which are monoclonal antibodies targeting IGF-1/2