PI3K pathway alterations in cancer: variations on a theme

Abstract

The high frequency of phosphoinositide 3-kinase (PI3K) pathway alterations in cancer has led to a surge in the development of PI3K inhibitors. Many of these targeted therapies are currently in clinical trials and show great promise for the treatment of PI3K-addicted tumors. These recent developments call for a re-evaluation of the oncogenic mechanisms behind PI3K pathway alterations. This pathway is unique in that every major node is frequently mutated or amplified in a wide variety of solid tumors. Receptor tyrosine kinases upstream of PI3K, the p110 alpha catalytic subunit of PI3K, the downstream kinase, AKT, and the negative regulator, PTEN, are all frequently altered in cancer. In this review, we will examine the oncogenic properties of these genetic alterations to understand whether they are redundant or distinct and propose treatment strategies tailored for these genetic lesions.

Figure 1

The PI3K signaling axis. Activation of RTKs recruits PI3K directly or through adaptor proteins such as the GAB proteins. PI3K phosphorylates PIP2 to generate PIP3, which leads to AKT activation and activation of numerous effectors that regulate critical cellular functions in cancer cells. PTEN negatively regulates this process through dephosphorylation of PIP3. All major members of this signaling axis are frequently altered in cancer. PI3K, phosphoinositide 3-kinase; RTKs, receptor tyrosine kinases.

Figure 2

Possible models of oncogenicity. In model 1, genetic alterations in any of the PI3K pathway members lead to amplification of PI3K signaling. In model 2, alterations of RTKs, RAS or PTEN in addition to mutant PIK3CA lead to activation of non-overlapping pathways or disrupt negative feedback loops to enhance PI3K signaling. In model 3, oncogenic RAS leads to tumorigenesis via a mechanism independent of PI3K. In model 4, loss of PTEN leads to p53-dependent cellular senescence, which may be overcome by acquisition of an additional mutation in the pathway. In model 5, activation of PI3K is enhanced through interactions with oncogenic RAS. PI3K, phosphoinositide 3-kinase; RTKs, receptor tyrosine kinases.

Figure 3

PI3K in the tumor microenvironment. In tumor cells, PI3K plays an important role in tumor initiation, growth and proliferation. PI3K also plays a major role in endothelial and immune cells that support tumor growth, intravasation and invasion. Inhibition of PI3K may thus have the potential to inhibit formation of secondary-site metastases. PI3K, phosphoinositide 3-kinase.