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Targeting autophagy in cancer

Key Points

  • Macroautophagy (known as autophagy) is a highly regulated multi-step process that is involved in the bulk degradation of cellular proteins and organelles to provide macromolecular precursors that are recycled or that are used to fuel metabolic pathways.

  • Autophagy can be targeted for both stimulation and inhibition. Stimulation can be achieved through cellular stress (nutrient deprivation) and mTOR inhibition, and inhibition can be achieved through multiple targets both upstream (ULK1, Beclin 1 and VPS34 inhibitors) and downstream of the site of lysosomal fusion with the autophagosome.

  • Early clinical trials have demonstrated the feasibility and potential benefit of clinically inhibiting autophagy in multiple cancer types, including glioblastoma, pancreatic cancer, melanoma, sarcoma and multiple myeloma.

  • Ongoing studies are developing novel clinical biomarkers that can be used to monitor autophagy in patients, including electron microscopy evaluation of autophagosome number in peripheral blood mononuclear cells and tumour samples, LC3II and ATG13 puncta by immunohistochemistry, and novel imaging techniques that use positron emission tomography and metabolomics profiles.

  • The role of autophagy in regulating tumour immune responses is unclear, with arguments both for and against autophagy inhibition. Further research is needed to define the safety and utility of autophagy inhibition while also maximizing tumour immune responses for improved clinical outcomes.

  • Markers of autophagy dependence have the potential to identify patients who will best respond to autophagy inhibition therapy. Such markers include altered RAS signalling, BRAF mutations, signal transducer and activator of transcription 3 (STAT3) activation, autophagy-dependent secretion of interleukins and p53 status.

  • Autophagy can be an effective cancer escape mechanism and has been implicated in the development of resistance in multiple cancer types, including BRAF-mutated central nervous system (CNS) tumours and melanoma, non-small-cell lung cancer (NSCLC), bladder cancer and thyroid cancer. Combination therapy with autophagy inhibition in these cancers has the potential to reduce and reverse resistance to therapy.

Abstract

Autophagy is a mechanism by which cellular material is delivered to lysosomes for degradation, leading to the basal turnover of cell components and providing energy and macromolecular precursors. Autophagy has opposing, context-dependent roles in cancer, and interventions to both stimulate and inhibit autophagy have been proposed as cancer therapies. This has led to the therapeutic targeting of autophagy in cancer to be sometimes viewed as controversial. In this Review, we suggest a way forwards for the effective targeting of autophagy by understanding the context-dependent roles of autophagy and by capitalizing on modern approaches to clinical trial design.

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Figure 1: Timeline of the major discoveries that led to the successful targeting of autophagy in cancer.
Figure 2: Autophagy can be inhibited at multiple stages.
Figure 3: Molecular mechanism of autophagy dependence.

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Acknowledgements

Work in the authors' laboratories is supported by an elope, Inc. St Baldrick's Foundation Scholar Award, NIH/NCI (K08CA193982), and the Morgan Adams Foundation (J.M.L.). T32 CA190216-1 A1 (C.G.T.) and NIH CA150925, CA190170 and CA197887 (A.T.)

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Autophagic flux

A measure of the amount of cellular cargo and the rate at which it is degraded by the autophagy pathway.

Nutraceuticals

Food with a medicinal benefit.

Pharmacokinetic–pharmacodynamic parameters

(PK–PD parameters). The study of the time course of metabolism (PK) and the biochemical and physiological effects (PD) of a drug.

Maximum tolerated dose

(MTD). The highest dose of a treatment that is effective and that does not cause unacceptable side effects.

Myelosuppression

A decrease in bone marrow activity that results in fewer red blood cells, white blood cells and platelets.

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Levy, J., Towers, C. & Thorburn, A. Targeting autophagy in cancer. Nat Rev Cancer 17, 528–542 (2017). https://doi.org/10.1038/nrc.2017.53

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