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The present and future of PI3K inhibitors for cancer therapy

Abstract

Phosphoinositide 3-kinase (PI3K) signaling regulates cellular proliferation, survival and metabolism, and its aberrant activation is one of the most frequent oncogenic events across human cancers. In the last few decades, research has focused on the development of PI3K inhibitors, from preclinical tool compounds to the highly specific medicines approved to treat patients with cancer. Herein we discuss current paradigms for PI3K inhibitors in cancer therapy, focusing on clinical data and mechanisms of action. We also discuss current limitations in the use of PI3K inhibitors, including toxicities and mechanisms of resistance, with specific emphasis on approaches aimed at improving efficacy.

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Fig. 1: The PI3K–AKT pathway and the most common PIK3CA mutations in cancer.
Fig. 2: Non-cell-autonomous and cell-autonomous effects of PI3K inhibitors.
Fig. 3: Proposed approaches to increase the therapeutic index of PI3K inhibitors.

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Acknowledgements

We dedicate this Review to the memory of José Baselga, who was one of the pioneers in the clinical development of PI3K inhibitors. The work of P.C. is supported by an NCI K99/R00 Pathway to Independence Award (K99CA245122). E.T. is supported by grants from the JKTG Foundation, the Breast Cancer Research Alliance, the Institute of Cancer Informatics and an NCI K22 Transition to Independence Award. M.S. is supported by NIH grant P30CA008748.

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Correspondence to Jeffrey A. Engelman or Maurizio Scaltriti.

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Competing interests

P.C. is a founder and advisory board member of Venthera. E.T. has received honoraria for invited lectures at AstraZeneca and Oric Pharmaceuticals. M.S. is an AstraZeneca employee, holds AstraZeneca equity and is a cofounder of medendi.org. In the past 2 years, M.S. received research funding from Daiichi-Sankio, AstraZeneca, Menarini Ricerche, Puma Biotechnologies and Targimmune. J.A.E. was a Novartis employee and holds Novartis equity. J.A.E. is a cofounder of Treeline Biosciences.

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Peer review information Nature Cancer thanks Filip Janku, Cynthia Ma and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Castel, P., Toska, E., Engelman, J.A. et al. The present and future of PI3K inhibitors for cancer therapy. Nat Cancer 2, 587–597 (2021). https://doi.org/10.1038/s43018-021-00218-4

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