Targeting de novo lipogenesis and the Lands cycle induces ferroptosis in KRAS-mutant lung cancer.
Caterina BartolacciCristina AndreaniGonçalo ValeStefano BertoMargherita MelegariAnna Colleen CrouchDodge L BaluyaGeorge KembleKurt HodgesJacqueline StarrettKaterina PolitiSandra L StarnesDaniele LorenziniMaria Gabriela RasoLuisa Maren Solis SotoCarmen BehrensHumam KadaraBoning GaoIgnacio I WistubaJohn D MinnaJeffrey G McDonaldPier Paolo ScaglioniPublished in: Nature communications (2022)
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.
Keyphrases
- wild type
- cell death
- cell cycle arrest
- reactive oxygen species
- fatty acid
- simultaneous determination
- small cell lung cancer
- mass spectrometry
- induced apoptosis
- type diabetes
- cancer therapy
- liquid chromatography
- high resolution
- hydrogen peroxide
- tyrosine kinase
- rna seq
- drug delivery
- skeletal muscle
- tandem mass spectrometry
- oxidative stress
- signaling pathway
- insulin resistance