Insulin-like growth factor 1 receptor and hybrid insulin receptor-insulin-like growth factor 1 receptors (IGF1R and INSR-IGF1R hybrids)

The Insulin-like growth factor 1 receptor (IGF1R) is a transmembrane receptor tyrosine kinase (RTK) that mediates the mitogenic and anti-apoptotic effects of IGF-1 and IGF-2 [4, 7]. In tissues where both IGF1R and the insulin receptor (INSR) are expressed, they can form hybrid INSR-IGF1R receptors through the dimerization of their respective hemireceptors [2, 8]. These hybrid receptors are significant in cancer biology because they bind IGF-1 and IGF-2 with high affinity, potentially bypassing therapies that specifically target IGF1R homodimers [3, 9]. Activation of these receptors triggers downstream signaling through the PI3K/Akt and MAPK/ERK pathways, promoting tumor cell proliferation and survival [5, 10]. Therapeutic strategies include monoclonal antibodies that block ligand binding and promote receptor degradation, as well as small-molecule inhibitors that target the kinase domain [4, 7]. However, the high structural homology between IGF1R and INSR often leads to off-target metabolic effects, such as hyperglycemia and insulin resistance, which have limited the clinical success of many inhibitors [6, 11]. Teprotumumab is a notable exception, having received approval for the treatment of thyroid-associated ophthalmopathy [5].

Other names

IGF-1RCD221JTK13Insulin-like growth factor 1 receptorHybrid insulin receptorIR/IGF-1R hybridsINSR/IGF1R hybridsInsulin-like growth factor I receptor

Monoclonal antibody antagonism of ligand binding, induction of receptor internalization and degradation, and small-molecule inhibition of the intracellular tyrosine kinase domain [4, 7].