Mutations 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.
The central role of phosphoinositide 3-kinase (PI3K) activation in tumour cell biology has prompted a sizeable effort to target PI3K and/or downstream kinases such as AKT and mammalian target of rapamycin (mTOR) in cancer. However, emerging clinical data show limited single-agent activity of inhibitors targeting PI3K, AKT or mTOR at tolerated doses. One exception is the response to PI3Kδ inhibitors in chronic lymphocytic leukaemia, where a combination of cell-intrinsic and -extrinsic activities drive efficacy. Here, we review key challenges and opportunities for the clinical development of inhibitors targeting the PI3K–AKT–mTOR pathway. Through a greater focus on patient selection, increased understanding of immune modulation and strategic application of rational combinations, it should be possible to realize the potential of this promising class of targeted anticancer agents.
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The authors thank J. Oliner for critical review of the manuscript, and B. Vanhaesebroeck for sharing unpublished results. Research on PI3K and mTOR in David Fruman's laboratory is supported by US National Institutes of Health (NIH) grants CA158383 and AI099656, and the Cancer Center Support Grant P30CA62203 to University of California, Irvine (UC Irvine).
C.R. is an employee of Amgen Inc., a biopharmaceutical company discovering, developing and commercializing human therapeutics.
- Phosphoinositide 3-kinase
(PI3K). A lipid kinase that produces phosphatidylinositol-3,4,5-trisphosphate (PtdIns(3,4,5)P3; also known as PIP3), which is a key signalling lipid.
A serine/threonine kinase whose activation is dependent on phosphoinositide 3-kinase.
- Mammalian target of rapamycin
(mTOR). A serine/threonine kinase that functions in two distinct complexes: mTOR complex 1 (mTORC1) and mTORC2.
The human gene encoding the p110a catalytic isoform of phosphoinositide 3-kinase (PI3K). Gain-of-function mutations in PIK3CA are frequent in cancer.
- Phosphatase and tensin homolog
(PTEN). A lipid 3-phosphatase that opposes phosphoinositide 3-kinase (PI3K) signalling and is often disabled in cancer.
A family of small GTPases that are often mutated in cancer and activate phosphoinositide 3-kinase (PI3K) and other oncogenic signals.
Structural analogues of rapamycin that inhibit mammalian target of rapamycin (mTOR) but have altered pharmacological properties.
- Pan-PI3K inhibitors
Molecules that inhibit all class I phosphoinositide 3-kinase (PI3K) enzymes but are selective relative to other lipid and protein kinases.
- Basket trials
Clinical trials that enrol patients with tumours of diverse tissue and histological origin, but with a shared genetic signature (in this case, PI3K catalytic isoform p110α (PIK3CA)-mutant tumours).
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Fruman, D., Rommel, C. PI3K and cancer: lessons, challenges and opportunities. Nat Rev Drug Discov 13, 140–156 (2014). https://doi.org/10.1038/nrd4204
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