Quantitative Measurement of Functional Activity of the PI3K Signaling Pathway in Cancer.

Anja Van De Stolpe

doi:10.3390/cancers11030293

Abstract

The phosphoinositide 3-kinase (PI3K) growth factor signaling pathway plays an important role in embryonic development and in many physiological processes, for example the generation of an immune response. The pathway is frequently activated in cancer, driving cell division and influencing the activity of other signaling pathways, such as the MAPK, JAK-STAT and TGFβ pathways, to enhance tumor growth, metastasis, and therapy resistance. Drugs that inhibit the pathway at various locations, e.g., receptor tyrosine kinase (RTK), PI3K, AKT and mTOR inhibitors, are clinically available. To predict drug response versus resistance, tests that measure PI3K pathway activity in a patient sample, preferably in combination with measuring the activity of other signaling pathways to identify potential resistance pathways, are needed. However, tests for signaling pathway activity are lacking, hampering optimal clinical application of these drugs. We recently reported the development and biological validation of a test that provides a quantitative PI3K pathway activity score for individual cell and tissue samples across cancer types, based on measuring Forkhead Box O (FOXO) transcription factor target gene mRNA levels in combination with a Bayesian computational interpretation model. A similar approach has been used to develop tests for other signaling pathways (e.g., estrogen and androgen receptor, Hedgehog, TGFβ, Wnt and NFκB pathways). The potential utility of the test is discussed, e.g., to predict response and resistance to targeted drugs, immunotherapy, radiation and chemotherapy, as well as (pre-) clinical research and drug development.

Highlights

A limited number of signal transduction pathways are evolutionarily well conserved to control basic cellular processes, such as cell division, cell differentiation and migration [1,2,3]
Signaling pathways can be roughly categorized as hormone driven nuclear receptor pathways, developmental pathways (e.g., Wnt, Hedgehog, TGFβ, and Notch pathways), the inflammatory NFκB pathway, and the highly complex growth factor regulated signaling pathway network, in which the phosphoinositide 3-kinase (PI3K)-AKT-mTOR pathway is probably the most prominent, next to MAPK and JAK-STAT pathways [2,4,5,6,7,8,9,10,11]
In advanced prostate cancer we frequently identified a combination of an active PI3K pathway with the loss of TGFβ pathway activity [67]

Summary

Introduction

A limited number of signal transduction pathways are evolutionarily well conserved to control basic cellular processes, such as cell division, cell differentiation and migration [1,2,3]. Signaling pathways can be roughly categorized as hormone driven nuclear receptor pathways (e.g., androgen and estrogen receptor pathways), developmental pathways (e.g., Wnt, Hedgehog, TGFβ, and Notch pathways), the inflammatory NFκB pathway, and the highly complex growth factor regulated signaling pathway network, in which the phosphoinositide 3-kinase (PI3K)-AKT-mTOR pathway is probably the most prominent, next to MAPK and JAK-STAT pathways [2,4,5,6,7,8,9,10,11] These signaling pathways are core regulators of embryonic development and control important physiological processes, such as hematopoiesis and generation of an immune response, tissue regeneration, hair growth, and renewal of intestinal mucosa [11,12,13,14]. Control of their activity is typically altered or lost In cancer, this is exemplified by uncontrolled cell division compared to a strictly controlled balance between cell division and differentiation in the developing embryo, while distant metastasis can be seen as an uncontrolled version of cell migration during organ development [1,29]. These cancer characteristics constitute important hallmarks of cancer [22]

The PI3K Pathway in Oncology

Drugs to Modify the Activity of the PI3K Pathway

Measuring Functional PI3K Pathway Activity

Conclusions

Findings

Knowledge-based