Faculty, Staff and Student Publications
Publication Date
7-26-2022
Journal
Nature Communications
DOI
10.1038/s41467-022-31963-4
PMID
35882862
PMCID
PMC9325712
PubMedCentral® Posted Date
7-26-2022
PubMedCentral® Full Text Version
Post-print
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.
Keywords
Ferroptosis, Humans, Lipid Metabolism, Lipogenesis, Lung Neoplasms, Phosphatidylcholines, Proto-Oncogene Proteins p21(ras)
Published Open-Access
yes
Recommended Citation
Bartolacci, Caterina; Andreani, Cristina; Vale, Gonçalo; et al., "Targeting De Novo Lipogenesis and the Lands Cycle Induces Ferroptosis in KRAS-Mutant Lung Cancer" (2022). Faculty, Staff and Student Publications. 2886.
https://digitalcommons.library.tmc.edu/uthgsbs_docs/2886
Correction
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