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

Mylène Tajan, Marc Hennequart, Eric C. Cheung, Fabio Zani, Andreas K. Hock, Nathalie Legrave, Oliver D. K. Maddocks, Rachel A. Ridgway, Dimitris Athineos, Alejandro Suárez-Bonnet, Robert L. Ludwig, Laura Novellasdemunt, Nikolaos Angelis, Vivian S. W. Li, Georgios Vlachogiannis, Nicola Valeri, Nello Mainolfi, Vipin Suri, Adam Friedman, Mark Manfredi, Karen Blyth, Owen J. Sansom and Karen H. Vousden ()
Additional contact information
Mylène Tajan: The Francis Crick Institute
Marc Hennequart: The Francis Crick Institute
Eric C. Cheung: The Francis Crick Institute
Fabio Zani: The Francis Crick Institute
Andreas K. Hock: Cancer Research UK Beatson Institute
Nathalie Legrave: The Francis Crick Institute
Oliver D. K. Maddocks: Institute of Cancer Sciences, University of Glasgow
Rachel A. Ridgway: Cancer Research UK Beatson Institute
Dimitris Athineos: Cancer Research UK Beatson Institute
Alejandro Suárez-Bonnet: The Royal Veterinary College
Robert L. Ludwig: The Francis Crick Institute
Laura Novellasdemunt: The Francis Crick Institute
Nikolaos Angelis: The Francis Crick Institute
Vivian S. W. Li: The Francis Crick Institute
Georgios Vlachogiannis: The Institute of Cancer Research
Nicola Valeri: The Institute of Cancer Research
Nello Mainolfi: Raze Therapeutics, Inc.
Vipin Suri: Raze Therapeutics, Inc.
Adam Friedman: Raze Therapeutics, Inc.
Mark Manfredi: Raze Therapeutics, Inc.
Karen Blyth: Cancer Research UK Beatson Institute
Owen J. Sansom: Cancer Research UK Beatson Institute
Karen H. Vousden: The Francis Crick Institute

Nature Communications, 2021, vol. 12, issue 1, 1-16

Abstract: 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.

Date: 2021
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DOI: 10.1038/s41467-020-20223-y

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