Non-small-cell lung cancer (NSCLC) with concurrent mutations in KRAS and the tumour suppressor LKB1 (KL NSCLC) is refractory to most therapies and has one of the worst predicted outcomes. Here we describe a KL-induced metabolic vulnerability associated with serine–glycine-one-carbon (SGOC) metabolism. Using RNA-seq and metabolomics data from human NSCLC, we uncovered that LKB1 loss enhanced SGOC metabolism via serine hydroxymethyltransferase (SHMT). LKB1 loss, in collaboration with KEAP1 loss, activated SHMT through inactivation of the salt-induced kinase (SIK)–NRF2 axis and satisfied the increased demand for one-carbon units necessary for antioxidant defence. Chemical and genetic SHMT suppression increased cellular sensitivity to oxidative stress and cell death. Further, the SHMT inhibitor enhanced the in vivo therapeutic efficacy of paclitaxel (first-line NSCLC therapy inducing oxidative stress) in KEAP1-mutant KL tumours. The data reveal how this highly aggressive molecular subtype of NSCLC fulfills their metabolic requirements and provides insight into therapeutic strategies.

KRAS 和肿瘤抑制基因 LKB1 (KL NSCLC) 同时突变的非小细胞肺癌 (NSCLC) 对大多数疗法均无效，并且是预测结果最差的癌症之一。在这里，我们描述了 KL 诱导的与丝氨酸-甘氨酸一碳（SGOC）代谢相关的代谢脆弱性。使用来自人类 NSCLC 的 RNA-seq 和代谢组学数据，我们发现 LKB1 缺失通过丝氨酸羟甲基转移酶 (SHMT) 增强 SGOC 代谢。 LKB1 缺失与 KEAP1 缺失共同作用，通过盐诱导激酶 (SIK)-NRF2 轴失活来激活 SHMT，并满足抗氧化防御所需的一碳单位不断增加的需求。化学和遗传 SHMT 抑制增加了细胞对氧化应激和细胞死亡的敏感性。此外，SHMT 抑制剂增强了紫杉醇（诱导氧化应激的一线 NSCLC 疗法）在 KEAP1 突变 KL 肿瘤中的体内治疗效果。这些数据揭示了这种高度侵袭性的非小细胞肺癌分子亚型如何满足其代谢需求，并为治疗策略提供了见解。