Treating cancer with phosphatidylinositol-3-kinase inhibitors: increasing efficacy and overcoming resistance

Marcia N Paddock,Seth J Field,Lewis C Cantley

doi:10.1194/jlr.s092130

Abstract

The discovery of the phosphatidylinositol-3-kinase (PI3K) pathway was a major advance in understanding growth factor signaling. The high frequency of PI3K pathway mutations in many cancers has encouraged a new field targeting cancer driver mutations. Although there have been many successes, targeting PI3K itself has proven challenging, in part because of its multiple isoforms with distinct roles. Despite promising preclinical results, development of PI3K inhibitors as pharmacologic anticancer agents has been limited by modest single-agent efficacy and significant adverse effects. If we could overcome these limitations, PI3K inhibitors would be a powerful cancer-fighting tool. Data from phase III clinical trials yields insight into some of the problems with PI3K inhibitors. Recent advances have shed light on the mechanisms of tumor resistance to PI3K inhibitors via feedback pathways that cause elevated insulin levels that then activate the same PI3K pathways that are the targets of inhibition. Improving our understanding of the complex regulatory feedback pathways that activate in response to PI3K inhibition will reveal ways to increase the efficacy of PI3K inhibitors and reduce adverse effects, increasing the usefulness of this class as a treatment option for multiple cancer types.

Highlights

The discovery of the phosphatidylinositol-3-kinase (PI3K) pathway was a major advance in understanding growth factor signaling
As an example of the role of PI3K in growth factor signaling, when a receptor tyrosine kinase (RTK) is activated, such as the InsR, it recruits insulin receptor substrate 1, which undergoes tyrosine phosphorylation on multiple Y-X-X-M motifs that in turn interact with the SH2 domains of p85 to change PI3K conformation, while recruiting it to the substrate-rich plasma membrane, resulting in robust synthesis of PIP3 (Fig. 1)
PI3K inhibitors in cancer 749 increased risk of death in patients with higher BMI, including cervical, kidney, pancreas, and esophageal cancer [22]. One explanation for these observations is that insulin resistance, often associated with obesity, results in high circulating insulin levels that activate PI3K pathways in tumors, independent of PIK3CA mutations

Summary

Introduction

The discovery of the phosphatidylinositol-3-kinase (PI3K) pathway was a major advance in understanding growth factor signaling. As an example of the role of PI3K in growth factor signaling, when a RTK is activated, such as the InsR, it recruits insulin receptor substrate 1, which undergoes tyrosine phosphorylation on multiple Y-X-X-M motifs that in turn interact with the SH2 domains of p85 to change PI3K conformation, while recruiting it to the substrate-rich plasma membrane, resulting in robust synthesis of PIP3 (Fig. 1). In this and another trial combining buparlisib with lapatinib as a HER2/epidermal growth factor receptor inhibitor, each had one complete response (2–4%) as well as evidence of clinical response in several patients, suggesting activity in select patients [19].

Results

Conclusion