Targeting PI3K: A New Generation of Agents Emerges

Jane de Lartigue, PhD
Published: Thursday, Dec 05, 2013

Basic Elements of PI3K Pathway

Basic Elements of PI3K Pathway

This figure depicts key players in the PI3K/Akt/mTOR cellsignaling network, including kinases, multiproteins, and the phosphatase PTEN.

The phosphatidylinositol 3-kinase (PI3K) pathway is frequently deregulated in cancer at multiple different points, and has therefore emerged as one of the most deeply explored cell-signaling networks in oncogenic research. Yet currently, the only FDA-approved PI3K pathway inhibitors target a single node of this pathway, the mammalian target of rapamycin (mTOR). The substantial complexity of the PI3K pathway, driven by feedback loops and crosstalk with other signaling pathways, drives a significant amount of resistance to these therapies.

A broader array of PI3K pathway-targeting agents are now beginning to undergo clinical testing, including inhibitors of the central enzyme PI3K, and there is much interest in the potential antitumor efficacy of these next-generation agents in a variety of different cancers, as well as their role in overcoming resistance to other therapies driven by the activation of the PI3K pathway.

Oncogenic Potential of the PI3K Pathway

The PI3Ks are a large family of kinases that function as intracellular messengers to orchestrate an array of important cellular processes, such as growth, survival, and metabolism. The PI3K family is divided into three classes, each of which has a distinct structure, distribution in the cell, and mechanism of action. The class I PI3Ks are the most widely implicated in the development of cancer.

Typically activated by receptor tyrosine kinases (RTKs) or G proteincoupled receptors (GPCRs), the class I PI3Ks are responsible for the conversion of the membrane lipid phosphatidylinositol- 4,5-bisphosphate (more commonly known as PIP2) into phosphatidylinositol-3,4,5- trisphosphate (PIP3), via addition of a phosphate group to the 3’ position of its inositol ring. PIP3 then binds to and activates a host of target intracellular proteins; perhaps most significant among them is the serine/threonine kinase Akt (also known as protein kinase B).

Akt, in turn, activates a range of downstream signaling targets, including another serine/threonine kinase, mTOR. A master regulator of protein synthesis and other important biological processes, mTOR functions as part of two different multiprotein complexes, mTORC1 and mTORC2. It is such an oncogenically relevant downstream target of this pathway that the network is often referred to as the PI3K/Akt/mTOR pathway. The conversion of PIP2 to PIP3 by PI3K is counterbalanced by the phosphatase PTEN (phosphatase and tensin homolog), which catalyzes the reverse reaction.

The class I PI3Ks are composed of a regulatory and a catalytic subunit (known as p85 and p110, respectively). There are several isoforms of each; for example, the catalytic subunits are p110α, β, δ, and g, encoded by the PIK3CA, PIK3CB, PIK3CD, and PIK3CG genes, respectively. p110α and β are ubiquitously expressed throughout the cell, while PI3Kg and δ are preferentially expressed in white blood cells.

The PI3K pathway is among the most heavily investigated in cancer from a therapeutic standpoint, a fact that is reflected by the wide number of agents now in clinical trials. The main reason for this interest is that almost every node of the pathway has been found to be altered in cancer. The most commonly observed alterations include mutation or amplification of the PIK3CA gene, loss of PTEN expression, or hyperactivation of RTKs.

First-Generation PI3K Pathway- Targeting Agents

The prototypical agents targeting the PI3K pathway were a naturally occurring PI3K inhibitor, wortmannin, and a morpholine derivative of quercetin, LY294002. These compounds were instrumental in defining the biological role of PI3K, but they demonstrated poor pharmacokinetics and thus had limited therapeutic potential.

The first agents to enter the clinic were those targeting the downstream effector mTOR. Rapamycin (sirolimus) is a naturally occurring compound isolated from the soil bacterium Streptomyces hydroscopius, a potent inhibitor of mTORC1. Limitations in the solubility and pharmacokinetic properties of rapamycin led to development of rapamycin analogues with improved characteristics, including temsirolimus and everolimus.


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