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

Abstract

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.

IGF2 and IGF1R in pediatric adrenocortical tumors: roles in metastasis and steroidogenesis

“…Moreover, IGF1R interacts with other receptor tyrosine kinases such as epidermal growth factor receptors (EGFRs), vascular endothelial growth factor receptor (VEGFR), mesenchymal-epithelial transition factor (MET), platelet-derived growth factor receptor (PDGFR), estrogen receptors (ER), and others, which are frequently found upregulated in cancer cells and may play a role in resistance to therapies anti-IGF1R. The activation of common downstream effectors through other receptors has provided new approaches regarding cotargeting strategies for anticancer therapies (Singh et al 2014, Brahmkhatri et al 2015.…”

The Influence of Exercise on the Insulin-like Growth Factor Axis in Oncology: Physiological Basis, Current, and Future Perspectives

“…Although these processes of cellular signaling and receptor activation are central to the development and growth of many tissues (13), activation of the IGF1R and subsequent signaling in cancerous cells is thought to promote tumorigenesis and progression (14). The strength of association between IGF1R signaling and carcinogenesis is such that pharmacologic methods of IGF1R signaling ablation are being actively pursued through preclinical and clinical trials as potential cancer treatments (14,15).…”

Adenovirus E4-ORF1 Dysregulates Epidermal Growth Factor and Insulin/Insulin-Like Growth Factor Receptors To Mediate Constitutive Myc Expression

“…Future studies will investigate the roles for these novel E4-ORF1 activities in Ad-infected normal human epithelial cells. As EGFR, InsR, IGF1R, and Myc are dysregulated in many human cancers (47)(48)(49), it will also be impor-tant to determine whether these cellular factors contribute to E4-ORF1-induced cellular transformation and tumorigenesis.…”