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PI3K inhibitors are finally coming of age

An Author Correction to this article was published on 01 September 2021

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Abstract

Overactive phosphoinositide 3-kinase (PI3K) in cancer and immune dysregulation has spurred extensive efforts to develop therapeutic PI3K inhibitors. Although progress has been hampered by issues such as poor drug tolerance and drug resistance, several PI3K inhibitors have now received regulatory approval — the PI3Kα isoform-selective inhibitor alpelisib for the treatment of breast cancer and inhibitors mainly aimed at the leukocyte-enriched PI3Kδ in B cell malignancies. In addition to targeting cancer cell-intrinsic PI3K activity, emerging evidence highlights the potential of PI3K inhibitors in cancer immunotherapy. This Review summarizes key discoveries that aid the clinical translation of PI3Kα and PI3Kδ inhibitors, highlighting lessons learnt and future opportunities

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Fig. 1: General overview of signalling by class I PI3K isoforms.
Fig. 2: Key features of the interaction between PI3Ks and pan- and PI3Kα-selective inhibitors.
Fig. 3: Interactions of flat PI3Kδ-selective inhibitors with PI3Kδ.
Fig. 4: Interactions of selected propeller-shaped PI3Kδ-selective inhibitors with PI3Kδ.
Fig. 5: Multipronged anticancer activity of PI3Kα inhibition in solid tumours.
Fig. 6: Multipronged anticancer activity of PI3Kδ inhibition in cancer.

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Acknowledgements

This review is dedicated to the memory of Dr José Baselga, a champion of PI3K-related research and its clinical translation, who left us so prematurely. The authors thank S. Cosulich (AstraZeneca) for support, E. Toska (Johns Hopkins, Baltimore, USA) for feedback on Fig. 5a, P. Peréz-Galán and N. Serrat (IDIBAPS, Barcelona, Spain) for help with Fig. 6b, C. Burkhart (Novartis, Basel) and members of the B.V. group for excellent feedback on the manuscript, especially G. Gong, R. Madsen and A. Sullivan. Work in the B.V. laboratory is supported by PTEN Research, Cancer Research UK (C23338/A25722), the UK Biotechnology and Biological Sciences Research Council (BB/I007806/1, BB/M013278/1, BB/R017972/1) and the UK NIHR University College London Hospitals Biomedical Research Centre. J.R.B. receives research funding from NCI R01 CA 213442 (PI: J.R.B.), Gilead Sciences, Verastem and TG Therapeutics. Relevant work in the K.O. laboratory was from the Wellcome Trust (095691/Z/11/Z) and the Medical Research Council (MR/M012328/2). We apologize to all authors whose work could not be mentioned because of the limitations on the number of references that could be cited.

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Correspondence to Bart Vanhaesebroeck.

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B.V. is a consultant for iOnctura (Geneva, Switzerland), Venthera (Palo Alto, USA), Olema Pharmaceuticals (San Francisco, USA), Pharming (Leiden, Netherlands) and has received speaker fees from Gilead (Foster City, USA). M.W.D.P. is an employee and shareholder in AstraZeneca. J.R.B. has served as a consultant for AbbVie, Acerta, AstraZeneca, Beigene, Catapult, Dynamo Therapeutics, Genentech/Roche, Gilead, Juno/Celgene, Kite, Loxo, MEI Pharma, Novartis, Octapharma, Pfizer, Pharmacyclics, Sunesis, TG Therapeutics, Verastem; received honoraria from Janssen and Teva; received research funding from Gilead, Loxo, Sun and Verastem; and served on data safety monitoring committees for Morphosys and Invectys. F.A. received grants from AstraZeneca, Novartis, Pfizer, Eli Lilly, Daiichi Sankyo, Roche and served as consultant/speaker with fees donated to Institute Gustave Roussy, Paris, from AstraZeneca, Novartis, Pfizer, Lilly, Daiichi Sankyo, Roche and Sanofi. F.A. is a founder of Pegacsy. K.O. receives research funding from GlaxoSmithKline (Stevenage, UK) and has received consultancy and speaker fees from Gilead (Foster City, USA) and Karus Therapeutics (Oxford, UK). The other authors declare no competing interests.

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Targeted therapies

Therapies aimed to selectively modulate the molecules that are deregulated in disease (as opposed to non-targeted therapies, such as, for example, chemotherapy).

Intrinsic drug resistance

Drug resistance that exists in the cells before drug therapy.

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Drug resistance that develops in cells in response to a drug therapy to which the cells were originally sensitive.

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The cellular processes of generation and storage of energy and cell building blocks.

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The mechanisms of degradation of cellular components, to generate energy and recycle building blocks for macromolecules.

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A cellular ‘self-eating’ process that involves the sequestering of cytoplasmic material in double-membraned structures (called autophagosomes), followed by membrane trafficking to the lysosome for the degradation and recycling of cellular components.

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Commonly recurring mutations in a gene in disease, often altering key characteristics or function of the mutant protein.

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A form of programmed cell death that occurs during development and tissue remodellng, in which the cell internally degrades without rupturing the cell membrane, allowing the dead cells to be taken up and degraded by the surrounding cells.

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A condition in which one system influences and depends on another, and vice versa.

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A process of ongoing acquisition of genomic alterations, most often in cancer, including the gain or loss of whole chromosomes, as well as structural aberrations that range from point mutations to small-scale genomic alterations and gross chromosomal rearrangements.

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The complement of proteins secreted by cells in the extracellular environment.

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Stopping cells from proliferating, without killing them.

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The process of covalently attaching polymers of ADP-ribose to proteins by poly(ADP-ribose) polymerases (PARPs).

Antigen presentation

The process of displaying peptides by binding them to the major histocompatibilty complex on the surface of antigen-presenting cells, so that these antigens can be effectively recognized and bound by the antigen receptor on the surface of T lymphocytes.

Immune checkpoint

A surface protein of immune, and sometimes cancer, cells that helps to stimulate or inhibit the responsiveness of T lymphocytes to antigens.

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Functional interactions between tumour cells and the cells and tissues that surround them.

Transaminitis

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Vanhaesebroeck, B., Perry, M.W.D., Brown, J.R. et al. PI3K inhibitors are finally coming of age. Nat Rev Drug Discov 20, 741–769 (2021). https://doi.org/10.1038/s41573-021-00209-1

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