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- Title
Targeting de novo lipogenesis and the Lands cycle induces ferroptosis in KRAS-mutant lung cancer.
- Authors
Bartolacci, Caterina; Andreani, Cristina; Vale, Gonçalo; Berto, Stefano; Melegari, Margherita; Crouch, Anna Colleen; Baluya, Dodge L.; Kemble, George; Hodges, Kurt; Starrett, Jacqueline; Politi, Katerina; Starnes, Sandra L.; Lorenzini, Daniele; Raso, Maria Gabriela; Solis Soto, Luisa M.; Behrens, Carmen; Kadara, Humam; Gao, Boning; Wistuba, Ignacio I.; Minna, John D.
- Abstract
Mutant KRAS (KM), the most common oncogene in lung cancer (LC), regulates fatty acid (FA) metabolism. However, the role of FA in LC tumorigenesis is still not sufficiently characterized. Here, we show that KMLC has a specific lipid profile, with high triacylglycerides and phosphatidylcholines (PC). We demonstrate that FASN, the rate-limiting enzyme in FA synthesis, while being dispensable in EGFR-mutant or wild-type KRAS LC, is required for the viability of KMLC cells. Integrating lipidomic, transcriptomic and functional analyses, we demonstrate that FASN provides saturated and monounsaturated FA to the Lands cycle, the process remodeling oxidized phospholipids, such as PC. Accordingly, blocking either FASN or the Lands cycle in KMLC, promotes ferroptosis, a reactive oxygen species (ROS)- and iron-dependent cell death, characterized by the intracellular accumulation of oxidation-prone PC. Our work indicates that KM dictates a dependency on newly synthesized FA to escape ferroptosis, establishing a targetable vulnerability in KMLC. Mutant KRAS (KM) is associated with poor prognosis in lung cancer and reported to promote lipid metabolism. Here, the authors show that fatty acid synthesis, which provides lipids to repair oxidized phospholipids through the FASN-Lands cycle axis, is a specific vulnerability for KM lung cancer.
- Subjects
LUNG cancer; LIPID synthesis; LIPID metabolism; REACTIVE oxygen species; RAS oncogenes
- Publication
Nature Communications, 2022, Vol 13, Issue 1, p1
- ISSN
2041-1723
- Publication type
Article
- DOI
10.1038/s41467-022-31963-4