2. Academic Validation
  3. Concurrent Mutations in STK11 and KEAP1 Promote Ferroptosis Protection and SCD1 Dependence in Lung Cancer

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.
Corrin A Wohlhieter 1,  Allison L Richards 2,  Fathema Uddin 3,  Christopher H Hulton 4,  Àlvaro Quintanal-Villalonga 3,  Axel Martin 5,  Elisa de Stanchina 6,  Umeshkumar Bhanot 7,  Marina Asher 7,  Nisargbhai S Shah 3,  Omar Hayatt 6,  Darren J Buonocore 8,  Natasha Rekhtman 8,  Ronglai Shen 5,  Kathryn C Arbour 3,  Mark Donoghue 2,  John T Poirier 9,  Triparna Sen 10,  Charles M Rudin 11
Affiliations

Affiliations

  • 1 Graduate Program in Pharmacology, Weill Cornell Medicine, New York, NY 10021, USA.
  • 2 Marie-Josée and Henry R. Kravis Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
  • 3 Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
  • 4 Louis V. Gerstner Jr. Graduate School of Biomedical Sciences, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
  • 5 Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
  • 6 Antitumor Assessment Core, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
  • 7 Precision Pathology Biobanking Center, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
  • 8 Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
  • 9 Perlmutter Cancer Center, New York University Langone Health, New York, NY 10016, USA.
  • 10 Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Molecular Pharmacology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. Electronic address: sent@mskcc.org.
  • 11 Graduate Program in Pharmacology, Weill Cornell Medicine, New York, NY 10021, USA; Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Louis V. Gerstner Jr. Graduate School of Biomedical Sciences, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Molecular Pharmacology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. Electronic address: rudinc@mskcc.org.
PMID: 33264619 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.

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