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

Author

Listed:
  • 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)

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.

Suggested Citation

  • Caterina Bartolacci & Cristina Andreani & Gonçalo Vale & Stefano Berto & Margherita Melegari & Anna Colleen Crouch & Dodge L. Baluya & George Kemble & Kurt Hodges & Jacqueline Starrett & Katerina Poli, 2022. "Targeting de novo lipogenesis and the Lands cycle induces ferroptosis in KRAS-mutant lung cancer," Nature Communications, Nature, vol. 13(1), pages 1-19, December.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-31963-4
    DOI: 10.1038/s41467-022-31963-4
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    1. Jordi Barretina & Giordano Caponigro & Nicolas Stransky & Kavitha Venkatesan & Adam A. Margolin & Sungjoon Kim & Christopher J.Wilson & Joseph Lehár & Gregory V. Kryukov & Dmitriy Sonkin & Anupama Red, 2012. "Addendum: The Cancer Cell Line Encyclopedia enables predictive modelling of anticancer drug sensitivity," Nature, Nature, vol. 492(7428), pages 290-290, December.
    2. Minzhe Guo & Yina Du & Jason J. Gokey & Samriddha Ray & Sheila M. Bell & Mike Adam & Parvathi Sudha & Anne Karina Perl & Hitesh Deshmukh & S. Steven Potter & Jeffrey A. Whitsett & Yan Xu, 2019. "Single cell RNA analysis identifies cellular heterogeneity and adaptive responses of the lung at birth," Nature Communications, Nature, vol. 10(1), pages 1-16, December.
    3. Nicholas Yagoda & Moritz von Rechenberg & Elma Zaganjor & Andras J. Bauer & Wan Seok Yang & Daniel J. Fridman & Adam J. Wolpaw & Inese Smukste & John M. Peltier & J. Jay Boniface & Richard Smith & Ste, 2007. "RAS–RAF–MEK-dependent oxidative cell death involving voltage-dependent anion channels," Nature, Nature, vol. 447(7146), pages 865-869, June.
    4. Jordi Barretina & Giordano Caponigro & Nicolas Stransky & Kavitha Venkatesan & Adam A. Margolin & Sungjoon Kim & Christopher J. Wilson & Joseph Lehár & Gregory V. Kryukov & Dmitriy Sonkin & Anupama Re, 2012. "The Cancer Cell Line Encyclopedia enables predictive modelling of anticancer drug sensitivity," Nature, Nature, vol. 483(7391), pages 603-607, March.
    5. Vasanthi S. Viswanathan & Matthew J. Ryan & Harshil D. Dhruv & Shubhroz Gill & Ossia M. Eichhoff & Brinton Seashore-Ludlow & Samuel D. Kaffenberger & John K. Eaton & Kenichi Shimada & Andrew J. Aguirr, 2017. "Dependency of a therapy-resistant state of cancer cells on a lipid peroxidase pathway," Nature, Nature, vol. 547(7664), pages 453-457, July.
    6. Jude Canon & Karen Rex & Anne Y. Saiki & Christopher Mohr & Keegan Cooke & Dhanashri Bagal & Kevin Gaida & Tyler Holt & Charles G. Knutson & Neelima Koppada & Brian A. Lanman & Jonathan Werner & Aaron, 2019. "The clinical KRAS(G12C) inhibitor AMG 510 drives anti-tumour immunity," Nature, Nature, vol. 575(7781), pages 217-223, November.
    7. Jessalyn M. Ubellacker & Alpaslan Tasdogan & Vijayashree Ramesh & Bo Shen & Evann C. Mitchell & Misty S. Martin-Sandoval & Zhimin Gu & Michael L. McCormick & Alison B. Durham & Douglas R. Spitz & Zhiy, 2020. "Lymph protects metastasizing melanoma cells from ferroptosis," Nature, Nature, vol. 585(7823), pages 113-118, September.
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    1. Shuling Xu & Zhijun Zhu & Daniel G. Delafield & Michael J. Rigby & Gaoyuan Lu & Megan Braun & Luigi Puglielli & Lingjun Li, 2024. "Spatially and temporally probing distinctive glycerophospholipid alterations in Alzheimer’s disease mouse brain via high-resolution ion mobility-enabled sn-position resolved lipidomics," Nature Communications, Nature, vol. 15(1), pages 1-18, December.

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