Modulating the therapeutic response of tumours to dietary serine and glycine starvation

The non-essential amino acids serine and glycine are used in multiple anabolic processes that support cancer cell growth and proliferation (reviewed in ref. 1). While some cancer cells upregulate de novo serine synthesis, many others rely on exogenous serine for optimal growth. Restriction of dietary serine and glycine can reduce tumour growth in xenograft and allograft models. Here we show that this observation translates into more clinically relevant autochthonous tumours in genetically engineered mouse models of intestinal cancer (driven by Apc inactivation) or lymphoma (driven by Myc activation). The increased survival following dietary restriction of serine and glycine in these models was further improved by antagonizing the anti-oxidant response. Disruption of mitochondrial oxidative phosphorylation (using biguanides) led to a complex response that could improve or impede the anti-tumour effect of serine and glycine starvation. Notably, Kras-driven mouse models of pancreatic and intestinal cancers were less responsive to depletion of serine and glycine, reflecting an ability of activated Kras to increase the expression of enzymes that are part of the serine synthesis pathway and thus promote de novo serine synthesis.

非必需氨基酸丝氨酸（serine）与甘氨酸（glycine）参与多种合成代谢过程，以支持癌细胞的生长与增殖（相关综述见参考文献1）。尽管部分癌细胞会上调丝氨酸的从头合成，但多数其他癌细胞依赖外源性丝氨酸以维持最优生长。饮食限制丝氨酸与甘氨酸的摄入，可降低异种移植与同种移植模型中的肿瘤生长。本研究表明，上述发现可推广至更具临床相关性的基因工程小鼠自发肿瘤模型——包括由Apc失活驱动的肠癌模型，以及由Myc激活驱动的淋巴瘤模型。在这些模型中，通过饮食限制丝氨酸与甘氨酸所提升的生存率，若联合拮抗抗氧化应答，还可进一步提高。破坏线粒体氧化磷酸化（使用双胍类药物）会引发复杂的生物学应答，既可能增强也可能削弱丝氨酸与甘氨酸饥饿疗法的抗肿瘤效果。值得注意的是，由Kras激活驱动的胰腺癌与肠癌小鼠模型，对丝氨酸与甘氨酸耗竭的响应较弱，这反映出激活的Kras可上调丝氨酸合成通路相关酶的表达，从而促进丝氨酸的从头合成。