PI3K-AKT-mTOR Signaling Pathway

Canonical source: hsa04151

Pathway Overview

The PI3K-AKT-mTOR pathway regulates cell growth, survival, metabolism, and proliferation. Growth factors (e.g., insulin, EGF) activate receptor tyrosine kinases; PI3K generates PIP3; AKT phosphorylates downstream targets including mTOR. mTOR integrates nutrient and growth signals. The pathway is frequently dysregulated in cancer: PTEN loss, PIK3CA mutations, and EGFR amplification activate the pathway. TP53 can suppress mTOR via AMPK and other mechanisms; TP53 loss releases inhibition. EGFR is a key upstream driver in lung cancer. Therapeutic inhibitors target PI3K, AKT, mTOR, and EGFR. Obesity and diet influence pathway activity via insulin and nutrient sensing.

Environmental Triggers

Exposure	Trigger type
obesity-exposure	Hyperinsulinemia and adipokines activate PI3K-AKT; promotes cancer growth
diet-quality	Nutrient availability and insulin regulate mTOR
tobacco	Tobacco induces EGFR mutations in lung cancer

Genetic Modulation Points

Key genes

egfr— Receptor tyrosine kinase; activates PI3K; mutations common in lung cancer; therapeutic target
tp53— Tumor suppressor; can suppress mTOR via AMPK and other effectors; loss promotes pathway activation

Regulatory checkpoints

EGFR signaling— egfrTherapeutic target
mTOR complexTherapeutic target
TP53-mediated suppression— tp53

Tissue Specificity

lung— EGFR mutations in NSCLC

breast— PI3K pathway in breast cancer

colorectum— Pathway mutations in colorectal cancer

Disease Relevance

Linked diseases

lung-cancer— EGFR mutations drive NSCLC; PI3K-AKT activation
colorectal-cancer— PI3K and TP53 mutations; pathway dysregulation
breast-cancer— PIK3CA mutations; mTOR in hormone-resistant disease

Linked exposures

tobacco— Smoking associated with EGFR-mutant lung cancer
obesity-exposure— Obesity and hyperinsulinemia activate pathway; cancer risk

Pathway Diagram

Pathway diagram placeholder. A visual representation of this pathway will be integrated when available.

Evidence Nodes

Evidence for this pathway is derived from:

3 environmental trigger(s)
2 key gene(s)
3 linked disease(s)
2 linked exposure(s)

References

1.Lynch TJ, et al. (2004). EGFR and lung cancer. New England Journal of Medicine. doi:10.1056/NEJMoa040938
2.Fruman DA, Rommel C (2014). PI3K-AKT-mTOR in cancer. Nature Reviews Drug Discovery. doi:10.1038/nrd4201
3.Hopkins BD, et al. (2018). Obesity and PI3K pathway in cancer. Nature Reviews Cancer. doi:10.1038/s41568-018-0025-4
4.Feng Z, Levine AJ (2010). TP53 and mTOR crosstalk. Cell. doi:10.1016/j.cell.2010.06.001