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

The Insulin receptor–Insulin-like growth factor 1 receptor (INSR-IGF1R) hybrid receptor is a heterotetrameric cell-surface protein formed by the dimerization of one INSR alpha-beta hemireceptor and one IGF1R alpha-beta hemireceptor (Belfiore et al., 2009, Endocrine-Related Cancer). These hybrid receptors are prevalent in tissues expressing both parent receptors and are frequently upregulated in various malignancies, including breast, prostate, and thyroid cancers (Belfiore et al., 2017, Frontiers in Endocrinology). Functionally, they primarily act as high-affinity receptors for IGF-1 and IGF-2, effectively sequestering insulin receptor subunits into complexes that respond to growth factors rather than metabolic signals (Pandini et al., 2002, Clinical Cancer Research). This shift contributes to tumor cell proliferation and provides a mechanism for resistance against specific IGF1R-targeted monoclonal antibodies, which may not effectively inhibit hybrid signaling. Consequently, therapeutic development has shifted toward dual tyrosine kinase inhibitors like linsitinib, which target the highly conserved kinase domains of both INSR and IGF1R (Buck et al., 2010, Molecular Cancer Therapeutics). However, the clinical utility of such agents is often limited by metabolic toxicities, particularly hyperglycemia and hyperinsulinemia, resulting from the unintended inhibition of the metabolic functions of the homodimeric insulin receptor.

Other names

IR/IGF-1R hybrid receptorInsulin/IGF-1 hybrid receptorHybrid insulin receptorINSR/IGF1R hybrid

Inhibition of the intracellular tyrosine kinase domain to prevent autophosphorylation and downstream signaling (e.g., PI3K/Akt and MAPK pathways), or ligand-binding competition to prevent receptor activation (Belfiore et al., 2017, Frontiers in Endocrinology).