Insulin–PI3K signalling: an evolutionarily insulated metabolic driver of cancer

Abstract

Cancer is driven by incremental changes that accumulate, eventually leading to oncogenic transformation. Although genetic alterations dominate the way cancer biologists think about oncogenesis, growing evidence suggests that systemic factors (for example, insulin, oestrogen and inflammatory cytokines) and their intracellular pathways activate oncogenic signals and contribute to targetable phenotypes. Systemic factors can have a critical role in both tumour initiation and therapeutic responses as increasingly targeted and personalized therapeutic regimens are used to treat patients with cancer. The endocrine system controls cell growth and metabolism by providing extracellular cues that integrate systemic nutrient status with cellular activities such as proliferation and survival via the production of metabolites and hormones such as insulin. When insulin binds to its receptor, it initiates a sequence of phosphorylation events that lead to activation of the catalytic activity of phosphoinositide 3-kinase (PI3K), a lipid kinase that coordinates the intake and utilization of glucose, and mTOR, a kinase downstream of PI3K that stimulates transcription and translation. When chronically activated, the PI3K pathway can drive malignant transformation. Here, we discuss the insulin–PI3K signalling cascade and emphasize its roles in normal cells (including coordinating cell metabolism and growth), highlighting the features of this network that make it ideal for co-option by cancer cells. Furthermore, we discuss how this signalling network can affect therapeutic responses and how novel metabolic-based strategies might enhance treatment efficacy for cancer.

Key points

  • Systemic factors such as insulin activate the same signalling pathways as some of the most recurrent mutations in human cancer.

  • The phosphoinositide 3-kinase (PI3K) signalling cascade, which is activated by insulin, regulates cellular metabolism and cell fate decisions, including cell survival and proliferation.

  • High insulin levels can promote and sustain tumour growth.

  • Therapeutic targeting of the PI3K signalling cascade is subject to a variety of cellular and systemic feedback mechanisms, including acute insulin release.

  • Therapeutic approaches that reduce insulin exposure might increase the efficacy of agents that target the PI3K signalling axis.

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Fig. 1: Insulin regulates glycolysis through both AKT-dependent and AKT-independent mechanisms.
Fig. 2: Tissue and tumour response to insulin signalling.
Fig. 3: Analysis of the frequency of mutations in insulin–PI3K signalling.
Fig. 4: Mechanisms to inhibit insulin feedback in tumours.

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Acknowledgements

The authors would like to acknowledge the National Cancer Institute of the National Institutes of Health as research reported in this publication was supported under award numbers R35CA197588 (L.C.C.), R00CA230384 (B.D.H.) and K08CA230318 (M.D.G.). The authors would also like to acknowledge the support of the Grey Foundation’s Basser Initiative (L.C.C. and B.D.H.), a generous gift from The Roger and Susan Hertog Charitable Fund (L.C.C.) and the Lung Cancer Research Foundation (M.D.G.). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health or these foundations.

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B.D.H. and M.D.G. researched data for the article, contributed to discussion of its content, wrote the article and reviewed and edited the manuscript before submission. L.C.C. contributed to discussion of the content, wrote the article and reviewed and edited the manuscript before submission.

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Correspondence to Benjamin D. Hopkins.

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B.D.H., M.D.G. and L.C.C. are all founders of and consultants for Faeth, a company developing nutrition for cancer care. L.C.C. is a founder and member of the scientific advisory board and board of directors of Agios and Petra Pharma, which are companies developing drugs to target metabolism.

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Nature Reviews Endocrinology thanks F. Janku and the other, anonymous, reviewers for their contribution to the peer review of this work.

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The Cancer Genome Atlas (TCGA): https://www.cancer.gov/about-nci/organization/ccg/research/structural-genomics/tcga

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Hopkins, B.D., Goncalves, M.D. & Cantley, L.C. Insulin–PI3K signalling: an evolutionarily insulated metabolic driver of cancer. Nat Rev Endocrinol 16, 276–283 (2020). https://doi.org/10.1038/s41574-020-0329-9

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