Insulin-like growth factor 1 receptor (IGF-1R) signaling via Nuclear receptor coactivator 3 (SRC-3) (IGF-1R/SRC-3 axis)

The Insulin-like growth factor 1 receptor (IGF-1R) signaling via Steroid Receptor Coactivator 3 (SRC-3, also known as NCOA3 or AIB1) is a critical oncogenic axis that regulates cell proliferation, survival, and growth (24, 35). IGF-1R is a transmembrane receptor tyrosine kinase that, upon activation by its ligands IGF-1 or IGF-2, triggers downstream cascades such as the PI3K/AKT and Ras/MAPK pathways (7, 9). These pathways lead to the phosphorylation and activation of SRC-3, a potent transcriptional coactivator that is often considered rate-limiting for IGF-1 signaling (35, 45). Once activated, SRC-3 moves to the nucleus to enhance the transcriptional activity of various transcription factors, including the estrogen receptor (ER), androgen receptor (AR), and AP-1, thereby driving the expression of genes involved in cell cycle progression and anti-apoptosis (24, 34). This signaling axis is frequently overactivated or amplified in several cancers, most notably breast, prostate, and lung cancers, where it often mediates resistance to endocrine therapies and conventional chemotherapy (27, 31, 39). Therapeutic strategies targeting this axis include monoclonal antibodies and small-molecule inhibitors against IGF-1R, as well as emerging experimental inhibitors designed to degrade or inhibit SRC-3 (23, 26, 44).

Other names

IGF-1R/SRC-3 axisIGF-1R/NCOA3 signaling pathwayIGF-1R/AIB1 signaling axisInsulin-like growth factor 1 receptor / Steroid receptor coactivator 3 interaction

Inhibition of IGF-1R tyrosine kinase activity or ligand binding to prevent downstream phosphorylation and activation of SRC-3; direct inhibition or degradation of the SRC-3 coactivator to block oncogenic gene transcription.