Targeting de novo lipogenesis and the Lands cycle induces ferroptosis in KRAS-mutant lung cancer

• Published in: Nature communications Vol. 13; no. 1; pp. 4327 - 19
• Main 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., McDonald, Jeffrey G., Scaglioni, Pier Paolo
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 26.07.2022; Nature Publishing Group; Nature Portfolio
• Subjects: 13/106; 38/89; 49/91; 631/67/1059/602; 631/67/1612/1350; 631/67/2327; 64/110; 64/60; 82/16; 82/58; 96/31; 96/34; 96/63; Cell death; Fatty acids; Ferroptosis; Ferroptosis - genetics; Humanities and Social Sciences; Humans; K-Ras protein; Lipid metabolism; Lipid Metabolism - genetics; Lipids; Lipogenesis; Lipogenesis - genetics; Lung cancer; Lung Neoplasms - genetics; Lung Neoplasms - metabolism; Metabolism; multidisciplinary; Mutants; Oxidation; Phosphatidylcholines; Phospholipids; Proto-Oncogene Proteins p21(ras) - genetics; Proto-Oncogene Proteins p21(ras) - metabolism; Reactive oxygen species; Science; Science (multidisciplinary); Synthesis; Transcriptomics; Triglycerides; Tumorigenesis
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-022-31963-4

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.