Insulin-like growth factor 1 receptor (IGF-1R) and insulin receptor isoform A (IR-A) (IGF-1R/IR-A)

The Insulin-like growth factor 1 receptor (IGF-1R) and insulin receptor isoform A (IR-A) signaling pathway represents a critical therapeutic axis in oncology and metabolic regulation [1, 2]. IGF-1R is a transmembrane receptor tyrosine kinase that mediates the mitogenic and anti-apoptotic effects of IGF-1 and IGF-2 through the PI3K/Akt and MAPK pathways [1, 3]. IR-A is an alternatively spliced variant of the insulin receptor that lacks exon 11 and, unlike the metabolic IR-B isoform, exhibits high affinity for IGF-2, facilitating tumor growth and survival [3, 4]. These receptors can also assemble into IGF-1R/IR-A hybrid complexes, which further diversify the signaling potential of the IGF system in malignant cells [5]. In many cancers, IR-A is upregulated as a resistance mechanism to compensate for the pharmacological blockade of IGF-1R, necessitating the development of dual-target inhibitors [4, 6]. Pharmacological agents targeting this pathway include small-molecule tyrosine kinase inhibitors like linsitinib and monoclonal antibodies that either block ligand binding or trigger receptor internalization [6]. Clinical development of these agents has been complicated by the high structural similarity between IR-A and IR-B, often leading to off-target metabolic effects such as hyperglycemia [7]. Despite these challenges, the pathway remains a significant focus for precision medicine, particularly in tumors demonstrating high IR-A expression or IGF-2 dependence [3, 7].

Other names

IGF1R/INSR-A axisIGF-1R/IR hybrid receptorsInsulin-like growth factor signaling systemCD221/CD220 axisIGF-1R/IR-A pathway

Small-molecule inhibitors typically act as ATP-competitive antagonists of the intracellular tyrosine kinase domains of both IGF-1R and IR-A, while monoclonal antibodies block ligand binding to the extracellular domain or induce receptor internalization and degradation.