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

• DOI: 10.1038/s41467-022-31963-4
• Publication Date: 2022-07-27T12:49:42Z
• Authors: Caterina Bartolacci; Cristina Andreani; Gonçalo Vale; Stefano Berto; Margherita Melegari; Anna Colleen Crouch; Dodge L. Baluya; George Kemble; Kurt Hodges; Jacqueline Starrett; Katerina Politi; Sandra L. Starnes; Daniele Lorenzini; Maria Gabriela Raso; Luisa M. Solis Soto; Carmen Behrens; Humam Kadara; Boning Gao; Ignacio I. Wistuba; John D. Minna; Jeffrey G. McDonald; Pier Paolo Scaglioni
• Keywords: Lipogenesis

Abstract Mutant KRAS (KM), the most common oncogene in lung cancer (LC), regulates fatty acid (FA) metabolism. However, role of FA 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 FASN, rate-limiting enzyme synthesis, while being dispensable EGFR-mutant or wild-type LC, required for viability cells. Integrating lipidomic, transcriptomic functional analyses, FASN provides saturated monounsaturated to Lands cycle, process remodeling oxidized phospholipids, such as PC. Accordingly, blocking either cycle KMLC, promotes ferroptosis, reactive oxygen species (ROS)- iron-dependent cell death, characterized by intracellular accumulation oxidation-prone Our work indicates KM dictates dependency on newly synthesized escape establishing targetable vulnerability KMLC.