Concurrent Mutations in STK11 and KEAP1 Promote Ferroptosis Protection and SCD1 Dependence in Lung Cancer
Corrin A. Wohlhieter,
Allison L. Richards,
Fathema Uddin,
Christopher H. Hulton,
Àlvaro Quintanal-Villalonga,
Axel Martin,
Elisa de Stanchina,
Umeshkumar Bhanot,
Marina Asher,
Nisargbhai S. Shah,
Omar Hayatt,
Darren J. Buonocore,
Natasha Rekhtman,
Ronglai Shen,
Kathryn C. Arbour,
Mark Donoghue,
John T. Poirier,
Triparna Sen,
Charles M. Rudin
Affiliations
Corrin A. Wohlhieter
Graduate Program in Pharmacology, Weill Cornell Medicine, New York, NY 10021, USA
Allison L. Richards
Marie-Josée and Henry R. Kravis Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
Fathema Uddin
Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
Christopher H. Hulton
Louis V. Gerstner Jr. Graduate School of Biomedical Sciences, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
Àlvaro Quintanal-Villalonga
Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
Axel Martin
Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
Elisa de Stanchina
Antitumor Assessment Core, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
Umeshkumar Bhanot
Precision Pathology Biobanking Center, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
Marina Asher
Precision Pathology Biobanking Center, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
Nisargbhai S. Shah
Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
Omar Hayatt
Antitumor Assessment Core, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
Darren J. Buonocore
Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
Natasha Rekhtman
Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
Ronglai Shen
Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
Kathryn C. Arbour
Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
Mark Donoghue
Marie-Josée and Henry R. Kravis Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
John T. Poirier
Perlmutter Cancer Center, New York University Langone Health, New York, NY 10016, USA
Triparna Sen
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; Corresponding author
Charles M. Rudin
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; Corresponding author
Summary: 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.
