Role of PI3K/AKT/mTOR in Cancer Signaling

Abstract

Phosphatidylinositol 3-kinases (PI3K)/AKT/mammalian target of rapamycin (mTOR) pathway plays a crucial role in integrating a variety of extracellular stimuli to regulate growth and development. The pathway impacts diverse biological functions and is a prominent player in vital cellular processes such as growth and proliferation. PI3K/AKT/mTOR signaling has been implicated in the pathogenesis of various human cancers and is one of the most frequently deregulated pathways in cancer. Every major node of this signaling network is activated in a wide range of human tumors. Mechanisms for the pathway activation include activation of receptor tyrosine kinases (RTKs) upstream of PI3K, mutation or amplification of PIK3CA encoding p110α catalytic subunit of PI3K, mutation or loss of PTEN tumor suppressor gene, and mutation or amplification of AKT1. Once the pathway is activated, signaling through AKT can stimulate a series of substrates including mTOR which is involved in protein synthesis. The central role of the pathway in tumor cell biology has led to a sizeable ongoing effort in the development of pharmacological agents targeting different components of the pathway. Currently mTOR inhibitors are approved for several indications, and there are several novel PI3K/AKT/mTOR inhibitors in clinical trials, and some demonstrate promise for the treatment of hyperactivated PI3K tumors. A better understanding of the pathway oncogenic mechanisms, different ways in which the signaling network is upregulated, and properties of distinct PI3K/AKT/mTOR genetic alterations will guide future strategic approaches for rational combination therapies.