PI3K/Akt signaling pathway

The Phosphatidylinositol 3-kinase (PI3K)/Protein kinase B (PKB) pathway carries signals from cell-surface receptors to the machinery controlling growth, survival, metabolism, motility and angiogenesis, and is among the most frequently dysregulated pathways in human disease. Growth factors and cytokines acting through receptor tyrosine kinases recruit class I phosphoinositide 3-kinase, a lipid kinase built from a regulatory subunit and one of four catalytic subunits — p110α, p110β, p110δ and p110γ, encoded by PIK3CA, PIK3CB, PIK3CD and PIK3CG, whose distinct tissue distributions matter for which isoform a drug should hit. The activated enzyme phosphorylates PIP2 to PIP3, a membrane lipid that recruits AKT through its PH domain; PDK1 and mTORC2 then phosphorylate AKT at two sites to activate it fully. Active AKT phosphorylates Mtor, FOXO transcription factors, GSK-3β and the pro-apoptotic protein BAD, promoting protein synthesis and cell-cycle progression while suppressing the apoptotic program — which is why caspase-3 activation falls when the pathway is on and rises when it is blocked. The tumor suppressor PTEN removes the 3-phosphate from PIP3 and is the pathway's principal brake; its loss leaves AKT constitutively active.

Constitutive activation is accordingly a hallmark of many cancers, including lung adenocarcinoma, hepatocellular carcinoma, oral squamous cell carcinoma, breast cancer, glioma and multiple myeloma, where it supports epithelial–mesenchymal transition, metastasis, and resistance to agents such as cisplatin, gemcitabine and bortezomib. It intersects with cell-death programs beyond apoptosis, including ferroptosis, and with redox and inflammatory biology through reactive oxygen species handling, toll-like receptor signaling and NF-κB. It also runs alongside the RAS/MAPK, JAK-STAT and HIF-1α axes, and reciprocal relief of feedback between those cascades is the usual reason single-agent inhibition disappoints — one of several arguments for combination targeting.

Because the same pathway transmits insulin's metabolic signal, inhibiting it produces hyperglycemia as a mechanism-based class effect, which has constrained dosing throughout its development. Clinical progress has come from narrowing the target: isoform-selective PI3K inhibitors matched to a mutation, AKT inhibitors, and Mtor inhibitors such as everolimus, rather than pan-PI3K blockade. Inhibition is not always the goal — in wound healing, stem cell–based nerve repair, and mesenchymal stem cell or exosome-delivered growth factor therapies, PI3K/AKT activation is what is wanted. Upstream receptor tyrosine kinase inhibitors such as gefitinib reduce flux through the pathway indirectly, and natural products reported to modulate it, among them berberine and naringenin, remain a large preclinical literature whose in vivo relevance is mostly unsettled.