학술논문
Concurrent Mutations in STK11 and KEAP1 Promote Ferroptosis Protection and SCD1 Dependence in Lung Cancer
Document Type
article
Author
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
Source
Cell Reports, Vol 33, Iss 9, Pp 108444- (2020)
Subject
Language
English
ISSN
2211-1247
Abstract
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.