Human epidermal growth factor receptor 2 (HER2)–Phosphoinositide 3-kinase (PI3K)–AKT signaling pathway (HER2–PI3K–AKT pathway)

The Human epidermal growth factor receptor 2 (HER2)–Phosphoinositide 3-kinase (PI3K)–AKT signaling pathway is a central oncogenic axis that regulates critical cellular processes including growth, survival, and metabolism [8, 12]. The pathway is initiated by the activation of the HER2 receptor tyrosine kinase, which recruits and activates PI3K, leading to the production of PIP3 and subsequent phosphorylation of the serine/threonine kinase AKT [12, 14]. This pathway is frequently hyperactivated in various cancers, most notably HER2-positive breast cancer, through HER2 amplification, PIK3CA mutations, or PTEN loss [1, 8, 12]. Pharmacological targeting of this axis involves a range of agents, including monoclonal antibodies against HER2 (e.g., trastuzumab), small molecule tyrosine kinase inhibitors (e.g., lapatinib), and specific inhibitors of PI3K (e.g., alpelisib) and AKT (e.g., capivasertib) [1, 5, 15]. While these therapies have significantly improved clinical outcomes, the pathway remains a major site for the development of drug resistance, often necessitating combination treatment strategies to achieve durable responses [1, 3, 12].

Other names

HER2/PI3K/Akt axisErbB2-PI3K-Akt signaling pathwayHER2-AKT pathwayHER2/PI3K/Akt/mTOR pathway

Inhibition of HER2 dimerization and phosphorylation; inhibition of PI3K catalytic activity; allosteric or ATP-competitive inhibition of AKT; suppression of downstream mTOR signaling.