The type 1 insulin-like growth factor receptor signalling system and targeted tyrosine kinase inhibition in cancer

Abstract

Type 1 insulin-like growth factor receptor (IGF1R) signalling plays a critical role in normal cell growth, and in cancer development and progression. IGF1R and the insulin-like growth factors 1 and 2 (IGF1 and IGF2) are involved in various aspects of the malignant phenotype, suggesting that IGF1R is a potential target for cancer therapy. IGF1R is particularly important in the establishment and maintenance of the transformed phenotype, in mediating proliferation, and for the survival of tumour cells with anchorage-independent growth. IGF1R also exerts antiapoptotic activity and has a substantial influence on the control of the cell and body size. This property enables transformed cells to form macroscopic tumours and to survive the process of detachment required for metastasis. Pharmaceutical companies are investigating molecules that target IGF1R, including specific low molecular weight tyrosine kinase inhibitors and monoclonal antibodies, both of which possess various advantages and display different activity profiles. This review article focuses on the preclinical and clinical development of low molecular weight IGF1R tyrosine kinase inhibitors. It is critical to pursue a thorough molecular analysis of the metabolic activity of IGF1R to avoid possible side-effects of its inhibition.

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

“…Transphosphorylation of the IGF1R by the ligands IGF1 and IGF2 initiates cellular signaling through the MAPK and PI3K pathways, which facilitates DNA synthesis, cellular survival, proliferation, and differentiation in the target cell (8,12). 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).…”

Insulin deficiency induces rat renal mesangial cell dysfunction via activation of IGF-1/IGF-1R pathway

“…IGF-1R overexpression is observed in breast cancer, colon cancer, lung cancer, prostate cancer and pancreatic tumors. As a result, inhibition of the IGF-1R pathway has become one of therapeutic targets for the treatment of cancer, and there are studies showing that inhibition of IGF-1R can effectively alleviate the occurrence and development of tumors [26][27][28][29][30][31][32][33] . Abnormal proliferation in MCs and ECM accumulation are the main pathological changes of DN.…”

Knockdown of type I insulin-like growth factor receptor inhibits human colorectal cancer cell growth and downstream PI3K/Akt, WNT/β-catenin signal pathways

“…Once IRS1 becomes tyrosine phosphorylated, following recruits the regulatory and catalytic subunits of PI3K, ultimately results in the downstream phosphorylation of Akt, which involved in cell survival and apoptosis. It functions through enhancing the protein synthesis required for cell proliferation [17]. Nowadays, with more and more researches about IGF1R, many other regulatory factors has been presented, such as let-7d-5p, miR-493, miR-497 and tumor suppressor p53, klotho [18][19][20][21][22].…”