Insulin receptor (IR) and insulin-like growth factor receptor 1 (IGF-1R) signaling systems: novel treatment strategies for cancer

Insulin and insulin-like growth factor (IGF) signaling system, commonly known for fine-tuning numerous biological processes, has lately made its mark as a much sought-after therapeutic targets for diabetes and cancer. These receptors make an attractive anticancer target owing to their overexpression in variety of cancer especially in prostate and breast cancer. Inhibitors of IGF signaling were subjected to clinical cancer trials with the main objective to confirm the effectiveness of these receptors as a therapeutic target. However, the results that these trials produced proved to be disappointing as the role played by the cross talk between IGF and insulin receptor (IR) signaling pathways at the receptor level or at downstream signaling level became more lucid. Therapeutic strategy for IGF-1R and IR inhibition mainly encompasses three main approaches namely receptor blockade with monoclonal antibodies, tyrosine kinase inhibition (ATP antagonist and non-ATP antagonist), and ligand neutralization via monoclonal antibodies targeted to ligand or recombinant IGF-binding proteins. Other drug-discovery approaches are employed to target IGF-1R, and IR includes antisense oligonucleotides and recombinant IGF-binding proteins. However, therapies with monoclonal antibodies and tyrosine kinase inhibition targeting the IGF-1R are not evidenced to be satisfactory as expected. Factors that are duly held responsible for the unsuccessfulness of these therapies include (a) the existence of the IR isoform A overexpressed on a variety of cancers, enhancing the mitogenic signals to the nucleus leading to the endorsement of cell growth, (b) IGF-1R and IR that form hybrid receptors sensitive to the stimulation of all three IGF axis ligands, and (c) IGF-1R and IR that also have the potential to form hybrid receptors with other tyrosine kinase to potentiate the cellular transformation, tumorigenesis, and tumor vascularization. This mini review is a concerted effort to explore and fathom the well-recognized roles of the IRA signaling system in human cancer phenotype and the main strategies that have been so far evaluated to target the IR and IGF-1R.