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

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. MinnaJeffrey G McDonald, Pier P Scaglioni

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish (US)
Article number4327
JournalNature communications
Volume13
Issue number1
DOIs
StatePublished - Dec 2022

ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • General
  • Physics and Astronomy(all)

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