Concurrent loss-of-function mutations in STK11 and KEAP1 in lung adenocarcinoma (LUAD) are associated with aggressive tumor growth, resistance to available therapies, and early death. We investigated the effects of coordinate STK11 and KEAP1 loss by comparing co-mutant with single mutant and wild-type isogenic counterparts in multiple LUAD models. STK11/KEAP1 co-mutation results in significantly elevated expression of ferroptosis-protective genes, including SCD and AKR1C1/2/3, and resistance to pharmacologically induced ferroptosis. CRISPR screening further nominates SCD (SCD1) as selectively essential in STK11/KEAP1 co-mutant LUAD. Genetic and pharmacological inhibition of SCD1 confirms the essentiality of this gene and augments the effects of ferroptosis induction by erastin and RSL3. Together these data identify SCD1 as a selective vulnerability and a promising candidate for targeted drug development in STK11/KEAP1 co-mutant LUAD.

肺腺癌 (LUAD) 中STK11和KEAP1的同时功能丧失突变与肿瘤的侵袭性生长、对现有疗法的耐药性和过早死亡有关。我们通过比较多个 LUAD 模型中的共突变体与单突变体和野生型同基因对应物，研究了协调STK11和KEAP1丢失的影响。 STK11/KEAP1共突变导致铁死亡保护基因（包括SCD和AKR1C1/2/3 ）的表达显着升高，并对药物诱导的铁死亡产生抵抗力。 CRISPR 筛选进一步提名SCD (SCD1) 作为STK11/KEAP1共突变体 LUAD 中选择性必需的。 SCD1 的遗传和药理学抑制证实了该基因的重要性，并增强了erastin 和RSL3 诱导铁死亡的作用。这些数据共同表明 SCD1 是一种选择性脆弱性，也是STK11/KEAP1共突变体 LUAD 靶向药物开发的有希望的候选者。