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. Minna, Jeffrey G. McDonald and Pier Paolo Scaglioni ()
Additional contact information
Caterina Bartolacci: University of Cincinnati College of Medicine
Cristina Andreani: University of Cincinnati College of Medicine
Gonçalo Vale: The University of Texas Southwestern Medical Center
Stefano Berto: The University of Texas Southwestern Medical Center
Margherita Melegari: University of Cincinnati College of Medicine
Anna Colleen Crouch: The University of Texas MD Anderson Cancer Center
Dodge L. Baluya: Washington State University
George Kemble: Sagimet Biosciences
Kurt Hodges: University of Cincinnati College of Medicine
Jacqueline Starrett: Yale School of Medicine
Katerina Politi: Yale School of Medicine
Sandra L. Starnes: University of Cincinnati College of Medicine
Daniele Lorenzini: Fondazione IRCCS Istituto Nazionale dei Tumori di Milano
Maria Gabriela Raso: The University of Texas MD Anderson Cancer Center
Luisa M. Solis Soto: The University of Texas MD Anderson Cancer Center
Carmen Behrens: The University of Texas MD Anderson Cancer Center
Humam Kadara: The University of Texas MD Anderson Cancer Center
Boning Gao: The University of Texas Southwestern Medical Center
Ignacio I. Wistuba: The University of Texas MD Anderson Cancer Center
John D. Minna: The University of Texas Southwestern Medical Center
Jeffrey G. McDonald: The University of Texas Southwestern Medical Center
Pier Paolo Scaglioni: University of Cincinnati College of Medicine

Nature Communications, 2022, vol. 13, issue 1, 1-19

Abstract: 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.

Date: 2022
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DOI: 10.1038/s41467-022-31963-4

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