UC Irvine

Key PointsMutations that activate the phosphoinositide 3-kinase (PI3K) signalling network are nearly ubiquitous in human cancer.PI3K activation has central physiological roles in many normal cells and tissues, including those of the immune system.Small molecules have been generated that selectively inhibit PI3K, AKT or mammalian target of rapamycin (mTOR) with good pharmacological properties.As single agents, most PI3K–AKT–mTOR inhibitors are cytostatic rather than cytotoxic to cancer cells.Early results from clinical trials show limited activity of these agents as monotherapies, but a striking exception is GS-1101, which is a selective inhibitor of p110δ.Now is the time to re-evaluate strategies to develop and apply PI3K pathway inhibitors for treating cancer.This Review proposes four priorities to guide future efforts in translational and clinical research.The first is biomarker identification, which involves using next-generation sequencing to identify genetic correlates for rare responders.The second is haematological malignancies; following on the success of GS-1101, clinical trials of leukaemia and lymphoma provide advantages for pharmacodynamic monitoring and for harnessing the effects of pathway inhibitors on the tumour microenvironment.The third is immune effects, which involves taking advantage of the cell-extrinsic effects of PI3K–mTOR inhibitors that can enhance antitumour immunity under certain conditions.The last is combination trials; it is likely that PI3K pathway inhibitors will be most effective when applied in combination with other targeted inhibitors. Many such combinations are discussed.