The Francis Crick Institute, 1 Midland Road, London, NW1 1AT, UK.
Cancer Research UK Beatson Institute, Switchback Road, Glasgow, G61 1BD, UK.
Nat Commun. 2021 Jan 14;12(1):366. doi: 10.1038/s41467-020-20223-y.
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.
许多肿瘤细胞依赖于外源性丝氨酸和饮食中的丝氨酸和甘氨酸饥饿，可抑制这些癌症的生长并延长小鼠的存活时间。然而，许多机制促进了对这种治疗方法的抵抗，包括增强从头合成丝氨酸途径（SSP）酶的表达或激活驱动增强丝氨酸合成的致癌基因。在这里，我们表明，SSP 的第一步 PHGDH 的抑制与丝氨酸和甘氨酸耗竭合作，抑制一碳代谢和癌症生长。在体外，PHGDH 的抑制与丝氨酸饥饿相结合导致全局蛋白质合成缺陷，从而阻止 ATF-4 反应的激活，并更广泛地影响对氨基酸耗竭的保护应激反应。在体内，饮食和抑制剂的联合使用对对抗对饮食或药物单独治疗有抗药性的肿瘤具有治疗效果，并证明一碳可用性降低。然而，在体外完全耗尽可用丝氨酸后观察到的 ATF4 反应缺陷在小鼠中并未观察到，其中饮食中的丝氨酸和甘氨酸耗竭以及 PHGDH 抑制剂的治疗降低但并未消除丝氨酸。我们的结果表明，PHGDH 的抑制将增强富含丝氨酸的饮食的治疗效果。
