TY - JOUR
T1 - Targeting de novo lipogenesis and the Lands cycle induces ferroptosis in KRAS-mutant lung cancer
AU - Bartolacci, Caterina
AU - Andreani, Cristina
AU - Vale, Gonçalo
AU - Berto, Stefano
AU - Melegari, Margherita
AU - Crouch, Anna Colleen
AU - Baluya, Dodge L.
AU - Kemble, George
AU - Hodges, Kurt
AU - Starrett, Jacqueline
AU - Politi, Katerina
AU - Starnes, Sandra L.
AU - Lorenzini, Daniele
AU - Raso, Maria Gabriela
AU - Solis Soto, Luisa M.
AU - Behrens, Carmen
AU - Kadara, Humam
AU - Gao, Boning
AU - Wistuba, Ignacio I.
AU - Minna, John D.
AU - McDonald, Jeffrey G.
AU - Scaglioni, Pier Paolo
N1 - Funding Information:
The preliminary part of this work was done at UT Southwestern medical Center. We thank CPRIT RP140672, CPRIT RP1606552, The University of Cincinnati College of Medicine, NIH/NCI R01 CA259845-01A1 and The LCS Foundation (Ohio) (P.P.S.). Lung Cancer SPORE (P50CA70907) (J.D.M., P.P.S., J.W.S., K.H., I.I.W.), the Harold C. Simmons Cancer Center through NCI Cancer Center support grant and 2P30CA016672. J.G.M. is supported in part by NIH HL020948. Cancer Prevention and Research Institute of Texas CPRIT RP160652, The University of Texas MD Anderson Cancer Center. Y.T.M.A. 310 was funded in part by the Yale SPORE in Lung Cancer P50 CA 196530 (PI: Roy Herbst). We thank Dr. Monte Winslow for kindly providing the murine LSL-KRAS cell lines, John M. Shelton for helping set up LMD conditions, Dr. Ken Greis and Dr. Robert Ross at UC Proteomics and Metabolomics Laboratory to provide guidance and instrumentation for the HPLC-MS/MS experiments, Dr. Peter Pathrose for performing KRAS mutation analysis on human lung cancer samples, Dr. Maria F. Czyzyk-Krezeska and Dr. David Plas for critically revising the manuscript. G12D
Funding Information:
The preliminary part of this work was done at UT Southwestern medical Center. We thank CPRIT RP140672, CPRIT RP1606552, The University of Cincinnati College of Medicine, NIH/NCI R01 CA259845-01A1 and The LCS Foundation (Ohio) (P.P.S.). Lung Cancer SPORE (P50CA70907) (J.D.M., P.P.S., J.W.S., K.H., I.I.W.), the Harold C. Simmons Cancer Center through NCI Cancer Center support grant and 2P30CA016672. J.G.M. is supported in part by NIH HL020948. Cancer Prevention and Research Institute of Texas CPRIT RP160652, The University of Texas MD Anderson Cancer Center. Y.T.M.A. 310 was funded in part by the Yale SPORE in Lung Cancer P50 CA 196530 (PI: Roy Herbst). We thank Dr. Monte Winslow for kindly providing the murine LSL-KRASG12Dcell lines, John M. Shelton for helping set up LMD conditions, Dr. Ken Greis and Dr. Robert Ross at UC Proteomics and Metabolomics Laboratory to provide guidance and instrumentation for the HPLC-MS/MS experiments, Dr. Peter Pathrose for performing KRAS mutation analysis on human lung cancer samples, Dr. Maria F. Czyzyk-Krezeska and Dr. David Plas for critically revising the manuscript.
Publisher Copyright:
© 2022, The Author(s).
PY - 2022/12
Y1 - 2022/12
N2 - 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.
AB - 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.
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U2 - 10.1038/s41467-022-31963-4
DO - 10.1038/s41467-022-31963-4
M3 - Article
C2 - 35882862
AN - SCOPUS:85135102056
SN - 2041-1723
VL - 13
JO - Nature Communications
JF - Nature Communications
IS - 1
M1 - 4327
ER -