Targeting PI3K/Akt Pathway: 20 Years of Progress

OncologyLive, October 2011, Volume 12, Issue 10

This year marks more than 20 years of research into the phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathway.

Potential Combinatorial Strategies

Proximal/Distal Signaling Inhibition

Parallel/Dual Signaling Inhibition

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.

Despite this interest, the only PI3K/Akt-related agents to have made it to market thus far are those that target mTOR and upstream RTKs such as EGFR. However, that may be set to change. A host of small-molecule inhibitors directly targeting PI3K, Akt, and other key nodes in this pathway are at various stages of clinical development.

The discovery of oncogenic mutations in the PIK3CA gene and elucidation of crystal structures of the catalytic domain of different PI3K isoforms have aided in the development of more isoform-specific PI3K inhibitors. These include GS-1101 (Gilead Sciences, Inc), targeting the p110 delta isoform, which is in phase II clinical trials for chronic lymphocytic leukemia and non-Hodgkin lymphoma, and PX- 866 (Oncothyreon), targeting the p110 alpha isoform, in phase II trials for brain cancer.

Inhibitors targeting multiple isoforms of the class I PI3Ks (known as pan-PI3K inhibitors) are also in development, including BKM120 (Novartis) in phase II trials for uterine cancer and non-small cell lung cancer (NSCLC) and SAR245408 (sanofi-aventis), in phase II trials for uterine and breast cancer.

Specific Akt inhibitors are also in the pipeline, particularly perifosine (KRX-0401, Keryx Biopharmaceuticals, Inc), currently in phase III trials for multiple myeloma and CRC, with results due at the end of the year. Another Akt inhibitor is MK-2206 (Merck & Co), undergoing phase I clinical testing in advanced solid tumors. Thus far, there has been limited clinical response to these drugs as monotherapy, even among patients with PIK3CA and PTEN alterations. However, evidence suggests that these drugs may have the most clinical benefit when used in combination either with other PI3K/Akt inhibitors, with other targeted therapies, or with conventional treatments such as chemotherapy—and this has subsequently become an area of intensive research.


A PI3 kinase bound to an inhibitor .

Path of Least Resistance?

Experience with targeted agents against mTOR and RTKs has demonstrated that cancer cells are highly adept at keeping the PI3K/Akt pathway switched on despite inhibitor activity. Resistance to both targeted therapies and to conventional chemotherapy and radiation therapy is a major issue in the treatment of patients with cancer, and residual PI3K/Akt pathway activation has frequently been described in cells that have developed resistance to these therapies.

For example, studies have shown that PI3K plays a key role in resistance to HER2-directed agents such as the monoclonal antibody trastuzumab and tyrosine kinase inhibitor (TKI) lapatinib, and combination with PI3K/Akt-targeted agents has been observed to restore their therapeutic effects.

There is also substantial interest in the combination of PI3K/Akt agents with inhibitors of the mitogen-activated protein kinase (MAPK) pathway. A phase IB trial of Roche’s GDC-0973 (a MEK inhibitor) and GDC-0941 (a PI3K inhibitor) is underway and has shown signs of antitumor activity in patients with advanced solid tumors.

Furthermore, there is extensive crosstalk between PI3K/Akt and other important signaling pathways. As a result, the inhibition of mTOR inadvertently leads to feedback activation of Akt. For this reason, combining PI3K/Akt and mTOR-targeted agents may be particularly beneficial. In fact, dual PI3K/mTOR inhibitors are also under development, including BEZ235 (Novartis) and SAR245409 (sanofi-aventis), in phase II clinical trials for uterine and breast cancer, respectively.

The sheer variety of potential pairings of PI3K/ Akt inhibitors with other targeted agents and cytotoxic therapies means that choosing the appropriate combination, dosing, and scheduling for different indications will be a big challenge for clinicians in the future.

Jane de Lartigue, PhD, is a freelance medical writer and editor based in the United Kingdom.

Key Research

  • Bartlett JMS. Biomarkers and patient selection for PI3K/Akt/mTOR targeted therapies: current status and future directions. Clinical Breast Cancer Special Issue. 2010;10(suppl 3): S86-S95.
  • Holmes D. PI3K pathway inhibitors approach junction. Nat Rev Drug Discov. 2011;10: 563-564.
  • Luo J, Manning BD and Cantley LC. Targeting the PI3K-Akt pathway in human cancer: rationale and promise. Cancer Cell. 2003;4:257-262.
  • 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.
  • LoRusso PM, Boerner SA. The role of phosphoinositide 3-kinase in breast cancer: an overview. Clinical Breast Cancer. 2010;10(suppl 3):S56-S58.
  • Markman B, Atzori F, Pérez-García J, Tabernero J, Baselga J. Status of PI3K inhibition and biomarker development in cancer therapeutics. Annals of Oncology. 2010; 21:683-691.
  • Markman B, Dienstmann R, Tabernero J. Targeting the PI3K/Akt/mTOR pathway — beyond rapalogs. Oncotarget. 2010;1:530-543.