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An integrative approach unveils FOSL1 as an oncogene vulnerability in KRAS-driven lung and pancreatic cancer

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  • Adrian Vallejo

    (University of Navarra, Center for Applied Medical Research, Program in Solid Tumors and Biomarkers)

  • Naiara Perurena

    (University of Navarra, Center for Applied Medical Research, Program in Solid Tumors and Biomarkers)

  • Elisabet Guruceaga

    (University of Navarra, Center for Applied Medical Research, Proteomics, Genomics and Bioinformatics Core Facility)

  • Pawel K. Mazur

    (Stanford University School of Medicine
    Stanford University School of Medicine)

  • Susana Martinez-Canarias

    (University of Navarra, Center for Applied Medical Research, Program in Solid Tumors and Biomarkers)

  • Carolina Zandueta

    (University of Navarra, Center for Applied Medical Research, Program in Solid Tumors and Biomarkers)

  • Karmele Valencia

    (University of Navarra, Center for Applied Medical Research, Program in Solid Tumors and Biomarkers)

  • Andrea Arricibita

    (University of Navarra, Center for Applied Medical Research, Program in Solid Tumors and Biomarkers)

  • Dana Gwinn

    (Stanford University School of Medicine)

  • Leanne C. Sayles

    (Stanford University School of Medicine)

  • Chen-Hua Chuang

    (Stanford University School of Medicine
    Stanford University School of Medicine)

  • Laura Guembe

    (University of Navarra, Center for Applied Medical Research, Morphology Unit)

  • Peter Bailey

    (Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Garscube Estate)

  • David K. Chang

    (Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Garscube Estate
    West of Scotland Pancreatic Unit, Glasgow Royal Infirmary
    The Kinghorn Cancer Centre, Garvan Institute of Medical Research, University of New South Wales
    Bankstown Hospital)

  • Andrew Biankin

    (Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Garscube Estate
    West of Scotland Pancreatic Unit, Glasgow Royal Infirmary
    The Kinghorn Cancer Centre, Garvan Institute of Medical Research, University of New South Wales
    Bankstown Hospital)

  • Mariano Ponz-Sarvise

    (University of Navarra, Center for Applied Medical Research, Program in Solid Tumors and Biomarkers
    Clínica Universidad de Navarra)

  • Jesper B. Andersen

    (Biotech Research and Innovation Center, University of Copenhagen)

  • Purvesh Khatri

    (Stanford Institute for Immunity, Transplantation and Infection
    Stanford Center for Biomedical Informatics Research, Stanford University)

  • Aline Bozec

    (University of Erlangen-Nuremberg)

  • E. Alejandro Sweet-Cordero

    (Stanford University School of Medicine)

  • Julien Sage

    (Stanford University School of Medicine
    Stanford University School of Medicine)

  • Fernando Lecanda

    (University of Navarra, Center for Applied Medical Research, Program in Solid Tumors and Biomarkers
    IdiSNA, Navarra Institute for Health Research
    University of Navarra)

  • Silve Vicent

    (University of Navarra, Center for Applied Medical Research, Program in Solid Tumors and Biomarkers
    IdiSNA, Navarra Institute for Health Research
    University of Navarra)

Abstract

KRAS mutated tumours represent a large fraction of human cancers, but the vast majority remains refractory to current clinical therapies. Thus, a deeper understanding of the molecular mechanisms triggered by KRAS oncogene may yield alternative therapeutic strategies. Here we report the identification of a common transcriptional signature across mutant KRAS cancers of distinct tissue origin that includes the transcription factor FOSL1. High FOSL1 expression identifies mutant KRAS lung and pancreatic cancer patients with the worst survival outcome. Furthermore, FOSL1 genetic inhibition is detrimental to both KRAS-driven tumour types. Mechanistically, FOSL1 links the KRAS oncogene to components of the mitotic machinery, a pathway previously postulated to function orthogonally to oncogenic KRAS. FOSL1 targets include AURKA, whose inhibition impairs viability of mutant KRAS cells. Lastly, combination of AURKA and MEK inhibitors induces a deleterious effect on mutant KRAS cells. Our findings unveil KRAS downstream effectors that provide opportunities to treat KRAS-driven cancers.

Suggested Citation

  • Adrian Vallejo & Naiara Perurena & Elisabet Guruceaga & Pawel K. Mazur & Susana Martinez-Canarias & Carolina Zandueta & Karmele Valencia & Andrea Arricibita & Dana Gwinn & Leanne C. Sayles & Chen-Hua , 2017. "An integrative approach unveils FOSL1 as an oncogene vulnerability in KRAS-driven lung and pancreatic cancer," Nature Communications, Nature, vol. 8(1), pages 1-14, April.
    • Handle: RePEc:nat:natcom:v:8:y:2017:i:1:d:10.1038_ncomms14294
    DOI: 10.1038/ncomms14294
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    Cited by:

    1. Irati Macaya & Marta Roman & Connor Welch & Rodrigo Entrialgo-Cadierno & Marina Salmon & Alba Santos & Iker Feliu & Joanna Kovalski & Ines Lopez & Maria Rodriguez-Remirez & Sara Palomino-Echeverria & , 2023. "Signature-driven repurposing of Midostaurin for combination with MEK1/2 and KRASG12C inhibitors in lung cancer," Nature Communications, Nature, vol. 14(1), pages 1-19, December.
    2. Ming Yi & Ruoqing Zhu & Robert M Stephens, 2018. "GradientScanSurv—An exhaustive association test method for gene expression data with censored survival outcome," PLOS ONE, Public Library of Science, vol. 13(12), pages 1-28, December.
    3. Heathcliff Dorado García & Fabian Pusch & Yi Bei & Jennifer Stebut & Glorymar Ibáñez & Kristina Guillan & Koshi Imami & Dennis Gürgen & Jana Rolff & Konstantin Helmsauer & Stephanie Meyer-Liesener & N, 2022. "Therapeutic targeting of ATR in alveolar rhabdomyosarcoma," Nature Communications, Nature, vol. 13(1), pages 1-15, December.
    4. Sally J. Adua & Anna Arnal-Estapé & Minghui Zhao & Bowen Qi & Zongzhi Z. Liu & Carolyn Kravitz & Heather Hulme & Nicole Strittmatter & Francesc López-Giráldez & Sampada Chande & Alexandra E. Albert & , 2022. "Brain metastatic outgrowth and osimertinib resistance are potentiated by RhoA in EGFR-mutant lung cancer," Nature Communications, Nature, vol. 13(1), pages 1-17, December.
    5. Shigekazu Murakami & Shannon M. White & Alec T. McIntosh & Chan D. K. Nguyen & Chunling Yi, 2023. "Spontaneously evolved progenitor niches escape Yap oncogene addiction in advanced pancreatic ductal adenocarcinomas," Nature Communications, Nature, vol. 14(1), pages 1-20, December.

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