Serine synthesis pathway inhibition cooperates with dietary serine and glycine limitation for cancer therapy

Tajan, M. et al. (2021) Serine synthesis pathway inhibition cooperates with dietary serine and glycine limitation for cancer therapy. Nature Communications, 12, 366. (doi: 10.1038/s41467-020-20223-y) (PMID:33446657) (PMCID:PMC7809039)

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Abstract

Many tumour cells show dependence on exogenous serine and dietary serine and glycine starvation can inhibit the growth of these cancers and extend survival in mice. However, numerous mechanisms promote resistance to this therapeutic approach, including enhanced expression of the de novo serine synthesis pathway (SSP) enzymes or activation of oncogenes that drive enhanced serine synthesis. Here we show that inhibition of PHGDH, the first step in the SSP, cooperates with serine and glycine depletion to inhibit one-carbon metabolism and cancer growth. In vitro, inhibition of PHGDH combined with serine starvation leads to a defect in global protein synthesis, which blocks the activation of an ATF-4 response and more broadly impacts the protective stress response to amino acid depletion. In vivo, the combination of diet and inhibitor shows therapeutic efficacy against tumours that are resistant to diet or drug alone, with evidence of reduced one-carbon availability. However, the defect in ATF4-response seen in vitro following complete depletion of available serine is not seen in mice, where dietary serine and glycine depletion and treatment with the PHGDH inhibitor lower but do not eliminate serine. Our results indicate that inhibition of PHGDH will augment the therapeutic efficacy of a serine depleted diet.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Blyth, Professor Karen and Cheung, Mr Eric and Ridgway, Dr Rachel and Hock, Dr Andreas and Valeri, Dr Nicola and Maddocks, Professor Oliver and Athineos, Mr Dimitris and Vousden, Karen and Ludwig, Mr Robert and Sansom, Professor Owen
Authors: Tajan, M., Hennequart, M., Cheung, E. C., Zani, F., Hock, A. K., Legrave, N., Maddocks, O. D.K., Ridgway, R. A., Athineos, D., Suárez-Bonnet, A., Ludwig, R. L., Novellasdemunt, L., Angelis, N., Li, V. S.W., Vlachogiannis, G., Valeri, N., Mainolfi, N., Suri, V., Friedman, A., Manfredi, M., Blyth, K., Sansom, O. J., and Vousden, K. H.
College/School:College of Medical Veterinary and Life Sciences > Institute of Cancer Sciences
Journal Name:Nature Communications
Publisher:Nature Research
ISSN:2041-1723
ISSN (Online):2041-1723
Copyright Holders:Copyright © 2021 The Authors
First Published:First published in Nature Communications 12: 366
Publisher Policy:Reproduced under a Creative Commons License

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
171982Targeting Tumour Metabolism for Cancer Therapy and Diagnosis.Oliver MaddocksCancer Research UK (CRUK)C53309/A19702Institute of Cancer Sciences