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 ManfrediKaren Blyth, Owen J. Sansom, Karen H. Vousden*

*Corresponding author for this work

Research output: Contribution to journalArticleResearchpeer-review

96 Citations (Scopus)


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.

Original languageEnglish
Article number366
JournalNature Communications
Issue number1
Publication statusPublished - 1 Dec 2021
Externally publishedYes


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