Epidermal growth factor receptor-Phosphoinositide 3-kinase-Protein kinase B signaling pathway (EGFR-PI3K-AKT)

The Epidermal growth factor receptor-Phosphoinositide 3-kinase-Protein kinase B (EGFR-PI3K-AKT) signaling pathway is a central regulator of cellular growth, proliferation, survival, and metabolism [NIH, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10458345/]. The pathway is initiated when ligands such as EGF bind to the extracellular domain of EGFR, a receptor tyrosine kinase, leading to its dimerization and autophosphorylation [NIH, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8038159/]. This activation recruits PI3K to the plasma membrane, where it converts PIP2 to PIP3, a second messenger that facilitates the recruitment and activation of the serine/threonine kinase AKT [NIH, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10458345/]. Once active, AKT phosphorylates a wide array of downstream targets, including mTOR, to promote cell cycle progression and inhibit apoptosis [NIH, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4113518/]. Dysregulation of this axis is a frequent occurrence in human malignancies, often driven by EGFR overexpression or mutations, PIK3CA mutations, or the loss of the tumor suppressor PTEN [Wikipedia, https://en.wikipedia.org/wiki/Glioblastoma]. These alterations contribute to aggressive tumor phenotypes and are major drivers of resistance to various therapies [NIH, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8038159/]. Consequently, the pathway is a primary focus for drug development, with numerous approved inhibitors targeting EGFR (e.g., osimertinib), PI3K (e.g., alpelisib), and AKT (e.g., capivasertib) [NIH, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10458345/].

Other names

EGFR/PI3K/Akt axisErbB1-PI3K-Akt pathwayEGFR-PI3K-Akt-mTOR pathwayEpidermal growth factor receptor-Phosphoinositide 3-kinase-AKT signaling pathway

Inhibition of receptor tyrosine kinase (EGFR), lipid kinase (PI3K), and serine/threonine kinase (AKT) activities within the signaling cascade.