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PI3K inhibitors are finally coming of age

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

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