Concurrent Mutations in STK11 and KEAP1 Promote Ferroptosis Protection and SCD1 Dependence in Lung Cancer

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. [Display omitted] •STK11/KEAP1 co-mutation promotes cell proliferation, independent of KRAS status•NRF2 activity is enhanced in STK11/KEAP1 co-mutation beyond KEAP1 loss alone•STK11 and KEAP1 mutations each independently promote ferroptosis protection•SCD1 protects STK11/KEAP1 co-mutant LUAD from ferroptosis and is essential for survival Wohlhieter et al. explore the global changes in gene expression and oncogenic signaling pathways driven by concurrent loss of function in two tumor suppressor genes, STK11 and KEAP1. They identify a molecular vulnerability, in which co-mutant cells depend on ferroptosis protective mechanisms for survival, and highlight SCD1 as an essential gene and promising drug target.