Abstract
The insulin and insulin-like growth factor (IGF) system plays an important role in regulating normal cell proliferation and survival. However, the IGF system is also implicated in many malignancies, including breast cancer. Preclinical studies indicate several IGF blocking approaches, such as monoclonal antibodies and tyrosine kinase inhibitors, have promising therapeutic potential for treating diseases. Uniformly, phase III clinical trials have not shown the benefit of blocking IGF signaling compared to standard of care arms. Clinical and laboratory data argue that targeting Type I IGF receptor (IGF1R) alone may be insufficient to disrupt this pathway as the insulin receptor (IR) may also be a relevant cancer target. Here, we review the well-studied role of the IGF system in regulating malignancies, the limitations on the current strategies of blocking the IGF system in cancer, and the potential future directions for targeting the IGF system.
Highlights
Others, such as trastuzumab, the first targeted-therapy approved by FDA for breast cancer, were designed as recombinant monoclonal antibodies against HER2 [53]
Cell-based studies show that Gp2 variants inhibit insulin-mediated signaling activation and cell growth in several breast cancer cell lines, indicating Gp2 variants are able to block the function of insulin receptor (IR)
IGF1R has been investigated as a therapeutic target in treating cancer for decades
Summary
Insulin and IGF Receptor Function in Cancer. Int. Many growth factors bind and activate RTKs by inducing the receptor dimer formation [4]. Each half-receptor consists of an extracellular α-chain containing the ligand-binding domain and an intracellular β-chain with tyrosine kinase activities [5,6]. Once the growth factor ligand binds to the extracellular domain of the receptors, the intracellular tyrosine kinase domain (TKD) of one β-subunit phosphorylates its apposing strand resulting in receptor autophosphorylation. Phosphorylation and activation of adaptor proteins induce the activation of downstream signaling such as PI3K/Akt and MAPK pathways, regulating cell growth, survival, apoptosis, metabolism, and mediating normal physiological processes at both cellular level and systemic level [13]
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