Review Article | Published:

Targeting the PI3K pathway in cancer: are we making headway?

Nature Reviews Clinical Oncology volume 15, pages 273291 (2018) | Download Citation

Abstract

The PI3K–AKT–mTOR pathway is one of the most frequently dysregulated pathways in cancer and, consequently, more than 40 compounds that target key components of this signalling network have been tested in clinical trials involving patients with a range of different cancers. The clinical development of many of these agents, however, has not advanced to late-phase randomized trials, and the antitumour activity of those that have been evaluated in comparative prospective studies has typically been limited, or toxicities were found to be prohibitive. Nevertheless, the mTOR inhibitors temsirolimus and everolimus and the PI3K inhibitors idelalisib and copanlisib have been approved by the FDA for clinical use in the treatment of a number of different cancers. Novel compounds with greater potency and selectivity, as well as improved therapeutic indices owing to reduced risks of toxicity, are clearly required. In addition, biomarkers that are predictive of a response, such as PIK3CA mutations for inhibitors of the PI3K catalytic subunit α isoform, must be identified and analytically and clinically validated. Finally, considering that oncogenic activation of the PI3K–AKT–mTOR pathway often occurs alongside pro-tumorigenic aberrations in other signalling networks, rational combinations are also needed to optimize the effectiveness of treatment. Herein, we review the current experience with anticancer therapies that target the PI3K–AKT–mTOR pathway.

Key points

  • The PI3K–AKT–mTOR signalling pathway, which controls multiple cellular processes including metabolism, motility, proliferation, growth, and survival, is one of the most frequently dysregulated pathways in human cancers.

  • The PI3K–AKT–mTOR pathway can be aberrantly activated by multiple factors, including diverse oncogenic genomic alterations in PIK3CA, PIK3R1, PTEN, AKT, TSC1, TSC2, LKB1, MTOR, and other critical genes, which can serve as targets for anticancer therapy.

  • More than 40 inhibitors of the PI3K–AKT–mTOR signalling pathway have reached different stages of clinical development, but few — temsirolimus, everolimus, idelalisib, and copanlisib — have been approved for clinical use.

  • Limited single-agent activity, problematic levels of toxicity, and a lack of predictive biomarkers for treatment selection have all been major barriers to the clinical translation of agents that target components of the PI3K–AKT–mTOR pathway.

  • Novel compounds and dosing schedules that have fewer off-target effects need to be developed; efforts to identify biomarkers associated with clinical activity also need to be expanded beyond PIK3CA or PTEN alterations.

  • Finally, as demonstrated in patients with metastatic hormone-receptor-positive breast cancer, combination strategies might open viable paths to advancing PI3K–AKT–mTOR inhibitors from clinical studies to new standard-of-care treatments.

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Acknowledgements

The work of the authors has been supported by the Sheikh Khalifa Al Nahyan Ben Zayed Institute for Personalized Cancer Therapy, by the US National Institutes of Health (NIH) through the National Center for Advancing Translational Sciences (grant UL1 TR000371), and by an MD Anderson Cancer Center Support Grant (P30 CA016672). The authors thank J. Munch of the MD Anderson Department of Scientific Publications for editing the manuscript before submission.

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  1. Department of Investigational Cancer Therapeutics (Phase I Clinical Trials Program), The University of Texas MD Anderson Cancer Center, Houston, TX, USA.

    • Filip Janku
    • , Timothy A. Yap
    •  & Funda Meric-Bernstam

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Contributions

F.J. researched data for the article. All authors contributed to discussions of content and to writing, review, and editing of the manuscript.

Competing interests

F.J. has received research support from Genentech, Novartis, and Piqur and has served on scientific advisory boards for Novartis. T.A.Y. has been a member of the scientific advisory boards of AstraZeneca, Bristol-Myers Squibb, Clovis Oncology, EMD Serono, Ignyta, and Pfizer, has received research funding from AstraZeneca, Clearbridge BioMedics, and Vertex, and has received travel support from AstraZeneca, Bristol-Myers Squibb, EMD Serono, Janssen-Cilag, MSD Oncology, and Vertex. F.M.-B. has received research funding from Aileron, AstraZeneca, Bayer, Calithera, Curis, CytomX, Debiopharm, Effective Pharmaceuticals, Genentech, Jounce, Novartis, Pfizer, PUMA, Taiho, and Zymeworks and has served on advisory boards for ClearLight Diagnostics, Darwin Health, GRAIL, and Pieris.

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Correspondence to Filip Janku.

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DOI

https://doi.org/10.1038/nrclinonc.2018.28

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