Serine/glycine restriction extends survival in mouse models of lymphoma and intestinal cancer.

  • Major finding: Serine/glycine restriction extends survival in mouse models of lymphoma and intestinal cancer.

  • Concept: Enhanced de novo serine synthesis renders KRAS-driven tumors less sensitive to serine/glycine depletion.

  • Impact: Dietary restriction of serine and glycine may be beneficial in patients with some tumor types.

Tumors depend on the non-essential amino acids serine and glycine for optimal growth. To obtain the necessary serine and glycine, some cancer cells upregulate de novo serine synthesis, but other tumors depend on exogenous serine and the dietary restriction of serine and glycine can suppress tumor growth in mouse xenografts and allografts. Maddocks and colleagues tested the effects of dietary serine and glycine restriction in more clinically relevant autochthonous tumor models of lymphoma (Eμ-Myc) and Apc-defective intestinal tumors. In mice with pre-malignant lesions, adopting a serine and glycine free diet extended survival. Further, in mice with established tumors, serine and glycine restriction slowed tumor growth. Serine starvation promotes de novo serine synthesis, which diverts glycolytic intermediates from energy production, resulting in enhanced oxidative phosphorylation. Therefore, the effects of serine starvation can be enhanced by inhibition of oxidative phosphorylation. However, biguanide-mediated disruption of mitochondrial oxidative phosphorylation had mixed effects, enhancing the anti-tumor effects of serine/glycine restriction in the lymphoma model, also increasing toxicity, and slightly increasing the number of tumors in the intestinal cancer model. However, increasing levels of reactive oxygen species (ROS) further extended survival in combination with serine/glycine restriction, and as chemotherapy and radiotherapy can induce ROS, serine/glycine restriction may be beneficial in combination with standard therapies. In contrast to the antitumor effects of serine/glycine restriction in MYC-driven lymphoma and Apc-inactivation–driven intestinal cancer, KrasG12D-driven pancreatic and intestinal tumors were less sensitive to serine/glycine depletion due to a KRAS-mediated upregulation of enzymes involved in de novo serine synthesis. Taken together, these findings demonstrate that dietary restriction of serine and glycine can be beneficial in some tumor types, although active KRAS may confer resistance to the antitumor effects. Further, the antitumor effects of dietary serine and glycine restriction may be enhanced by therapies that induce ROS.

Maddocks ODK, Athineos D, Cheung EC, Lee P, Zhang T, van den Broek NJF, et al. Modulating the therapeutic response of tumours to dietary serine and glycine starvation. Nature 2017;544:372–6.