Insulin-like growth factor 1 receptor-Insulin receptor hybrid (Hybrid IGF1R-INSR) (Hybrid IGF1R-INSR)

Insulin-like growth factor 1 receptor-Insulin receptor hybrids are heterotetrameric complexes formed by the assembly of one IGF1R hemireceptor and one INSR hemireceptor (Belfiore et al., 2009). These hybrids occur naturally in tissues expressing both parent receptors and are frequently overexpressed in various malignancies, including breast, prostate, and lung cancers (Slaaby et al., 2006). Functionally, hybrid receptors behave more like IGF1R, binding IGF-1 and IGF-2 with high affinity while exhibiting significantly lower affinity for insulin, thereby promoting pro-survival and proliferative signaling through the PI3K/Akt and MAPK pathways (Morcavallo et al., 2012). In the context of metabolic disease, the formation of these hybrids can sequester INSR hemireceptors, potentially reducing the availability of insulin homoreceptors and contributing to insulin resistance (Belfiore et al., 2009). Therapeutically, they represent a significant challenge because they can mediate resistance to monoclonal antibodies that specifically target IGF1R homoreceptors, such as ganitumab (Pollak, 2012). Consequently, dual IGF1R/INSR inhibitors or certain small molecule tyrosine kinase inhibitors like linsitinib are often required to effectively block their activity in clinical settings.

Other names

Insulin-like growth factor 1 receptor/Insulin receptor hybridIGF-IR/IR hybrid receptorHybrid-RInsulin/IGF-1 hybrid receptorHR-AHR-B

Small molecule inhibition of the intracellular tyrosine kinase domain or monoclonal antibody-mediated blockade of the extracellular ligand-binding domain to prevent downstream signaling through the PI3K/Akt and MAPK pathways (Belfiore et al., 2009; Pollak, 2012).