Targeting PI3K/Akt Pathway: 20 Years of Progress

Jane de Lartigue, PhD
Published Online: Monday, November 21, 2011

Potential Combinatorial Strategies

Proximal/Distal Signaling Inhibition

Proximal/Distal Signaling Inhibition

Parallel/Dual Signaling Inhibition

Parallel/Dual Signaling Inhibition

Signaling Inhibition and Other Targeted Therapies

Signaling Inhibition and
Other Targeted Therapies

Approaches under study
related to the P13K/Akt pathway

The 3 panels illustrate ways in which FDAapproved and investigational agents may be combined. Agents aimed at receptor tyrosine kinases (RTK) and oncogenes may be combined with agents that inhibit the pathway at key junctures (top). Dual inhibition of parallel signaling pathways is another option (center). Agents also may be combined with histone deacetylase complex inhibition (HDACi) and other targeted therapies (bottom).


Adapted from LoPiccolo J, Blumenthal GM, Bernstein WB, Dennis PA. Targeting the PI3K/Akt/mTOR pathway: effective combinations and clinical considerations. Drug Resist Updat. 2008;11(1-2):32–50.
This year marks more than 20 years of research into the phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathway, an occasion that is being recognized with special conferences focusing on recent advances in this rapidly growing area of research.

The main reason for the interest in this pathway is clear: It is one of the most perturbed signaling pathways in human cancer, and an integral cog in a network of other high-profile signaling pathways.

The pathway plays a role in a number of targeted therapies approved for clinical use in the past decade, and promising new agents aimed directly at PI3K/Akt are on the horizon.

The PI3K/Akt Signaling Cascade

The PI3Ks are a large family typically divided into 3 classes. The majority of research has focused on the class I PI3Ks, and these have the best characterized role in human cancer. Class I PI3Ks are further subdivided into class IA and IB and are activated at the cell surface by 2 different kinds of membrane receptors: receptor tyrosine kinases (RTKs), such as epidermal growth factor receptor (EGFR), and G protein-coupled receptors, respectively. They are composed of a regulatory (p85) and catalytic (p110) subunit, and multiple different isoforms of each subunit exist.

Once a class I PI3K is activated, its key function is to regulate the production of a membrane lipid called phosphatidylinositol-3,4,5-trisphosphate (more commonly dubbed PIP3). PIP3 subsequently activates a number of different proteins within the cell, most importantly the serine/ threonine kinase Akt (also known as protein kinase B). The level of PIP3 is strictly regulated, and several lipid phosphatases act to counterbalance the effects of the PI3Ks, principally a protein called PTEN.

Activation of the PI3K/Akt pathway has many downstream effects indicative of its vital role in many aspects of normal cellular physiology, including cell growth and survival. The best studied target of PI3K/Akt signaling is the mammalian target of rapamycin (mTOR), so much so that it is frequently referred to as the PI3K/Akt/mTOR pathway.

The Most Perturbed Pathway in Human Cancer

We almost invariably find this pathway “switched on” in cancers since it is crucial to many aspects of cell growth and survival. This is reflected in the fact that it is the most perturbed pathway in human cancers. The frequency of alterations to components of this pathway observed in different types of cancers is second only to that observed for the tumor suppressor protein p53.

Common alterations include mutations in the PIK3CA gene, encoding the p110 catalytic subunit, which are observed in more than 50% of bowel cancers and 26% of all breast cancers, and loss of expression of PTEN, observed in more than 50% of all cancers, including glioma, melanoma, and prostate cancer. AKT amplification, mutation, and overexpression are found in head and neck, gastric, ovarian, pancreatic, and colorectal cancers (CRC).

Exploiting the Pathway for Cancer Drug Discovery

Components of the PI3K/Akt pathway make extremely promising drug targets since they play a key role in cell survival; are often kinases, and are therefore amenable to targeting with small-molecule inhibitors; and are found in many different types of cancer so that a targeted drug would have multiple applications.

As a result, it has been a major focus of research and cancer drug development by a multitude of pharmaceutical companies and academic centers. More than 300 presentations on PI3K alone were given at the 2011 Association of Clinical Research Professionals conference in Seattle, Washington, in May, indicating that interest has not waned in the 2 decades since its discovery.

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