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

Cell Rep. 2020 Dec 1;33(9):108444. doi: 10.1016/j.celrep.2020.108444.

Abstract

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.

Keywords: AKR1C1; CRISPR; KEAP1; LKB1; NSCLC; SCD1; STK11; ferroptosis.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • AMP-Activated Protein Kinase Kinases / genetics*
  • AMP-Activated Protein Kinase Kinases / metabolism
  • Ferroptosis / genetics*
  • Humans
  • Kelch-Like ECH-Associated Protein 1 / metabolism
  • Lung Neoplasms / genetics*
  • Lung Neoplasms / metabolism
  • Lung Neoplasms / pathology
  • Mutation
  • Stearoyl-CoA Desaturase / genetics*
  • Stearoyl-CoA Desaturase / metabolism

Substances

  • KEAP1 protein, human
  • Kelch-Like ECH-Associated Protein 1
  • SCD1 protein, human
  • Stearoyl-CoA Desaturase
  • STK11 protein, human
  • AMP-Activated Protein Kinase Kinases