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.

许多肿瘤细胞表现出对外源丝氨酸和膳食丝氨酸和甘氨酸的依赖性，饥饿可以抑制这些癌症的生长并延长小鼠的生存期。然而，许多机制会促进对这种治疗方法的抵抗，包括增强丝氨酸从头合成途径（SSP）酶的表达或驱动增强丝氨酸合成的癌基因的激活。在这里，我们表明，抑制 PHGDH（SSP 的第一步）与丝氨酸和甘氨酸消耗协同抑制一碳代谢和癌症生长。在体外，抑制 PHGDH 与丝氨酸饥饿相结合会导致整体蛋白质合成缺陷，从而阻止 ATF-4 反应的激活，并更广泛地影响对氨基酸消耗的保护性应激反应。在体内，饮食和抑制剂的组合显示出对单独饮食或药物具有抗性的肿瘤的治疗功效，并有证据表明一碳可用性降低。然而，在体外观察到的可用丝氨酸完全耗尽后 ATF4 反应的缺陷在小鼠中并未观察到，其中膳食丝氨酸和甘氨酸耗尽以及用 PHGDH 抑制剂治疗降低了丝氨酸，但并未消除丝氨酸。我们的结果表明，抑制 PHGDH 将增强丝氨酸耗尽饮食的治疗效果。