Current State and Future Challenges for PI3K Inhibitors in Cancer Therapy

Abstract

The phosphoinositide 3 kinase (PI3K)-protein kinase B (PKB/AKT)-mammalian target of the rapamycin (mTOR) axis is a key signal transduction system that links oncogenes and multiple receptor classes which are involved in many essential cellular functions. Aberrant PI3K signalling is one of the most commonly mutated pathways in cancer. Consequently, more than 40 compounds targeting key components of this signalling network have been tested in clinical trials among various types of cancer. As the oncogenic activation of the PI3K/AKT/mTOR pathway often occurs alongside mutations in other signalling networks, combination therapy should be considered. In this review, we highlight recent advances in the knowledge of the PI3K pathway and discuss the current state and future challenges of targeting this pathway in clinical practice.

Keywords: PI3K inhibitors; clinical trial; mutations; target therapy.

Figure 1

The PI3K/AKT/mTOR pathway is involved in tumorigenesis and cancer progression. After being activated by RTKs, GPCR or RAS, PI3K catalyzes the phosphorylation of PIP2 to generate PIP3, which binds and recruits AKT and PDK1. Furthermore, by activating NF-κB and inducing the secretion of MMP, AKT promotes cell invasion while increasing the level of cyclin D1, leading to cell cycle progression. Ultimately, Akt promotes cell growth by phosphorylation of the downstream mTORC1, which activates p70S6K-S6 and inhibits 4E-BP1, resulting in protein synthesis and cell growth. Indeed, mTORC2 activates AKT itself. On the other hand, PTEN exerts its role in modulating the PI3K pathway by suppressing PIP2 to PIP3 conversion. Together with tuberous sclerosis protein 1 (TSC1) and TSC2, PTEN is the main negative regulator of the pathway. Simultaneously, activation of the growth factor receptor tyrosine kinases and G protein-coupled receptors induces RAS/RAF/MEK/ERK signalling, and ERK activation can further contribute to mTORC1 activation.

Figure 2

Summary of the complex phosphatidylinositol-3-kinase (PI3K)/AKT/mTOR signalling pathway and inhibitors.