Current State and Future Challenges for PI3K Inhibitors in Cancer Therapy

SIMPLE SUMMARY: Phosphatidylinositol 3-kinase (PI3K) is a key regulator of many cellular processes and its hyperactivation promotes tumor cell growth and survival. A broad evaluation of the upstream and downstream nodes of its pathway allowed the discovery of several PI3K inhibitors (PI3Ki) with anti-tumor activity. However, the highly intrinsic toxicity and the onset of therapeutic resistance can limit their clinical application. To increase the antitumor effect and the therapeutic index, combination strategies and new dosing schedules have been investigated. However, further efforts are necessary to discover potentially actionable genetic alterations towards the goal of precision medicine. 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.