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The integrated stress response is tumorigenic and constitutes a therapeutic liability in KRAS-driven lung cancer

Author

Listed:
  • Nour Ghaddar

    (Sir Mortimer B. Davis-Jewish General Hospital
    McGill University)

  • Shuo Wang

    (Sir Mortimer B. Davis-Jewish General Hospital)

  • Bethany Woodvine

    (University of Leicester
    University of Cambridge)

  • Jothilatha Krishnamoorthy

    (Sir Mortimer B. Davis-Jewish General Hospital)

  • Vincent Hoef

    (Karolinska Institute)

  • Cedric Darini

    (Sir Mortimer B. Davis-Jewish General Hospital)

  • Urszula Kazimierczak

    (Sir Mortimer B. Davis-Jewish General Hospital
    Poznan University of Medical Sciences)

  • Nicolas Ah-son

    (Sir Mortimer B. Davis-Jewish General Hospital)

  • Helmuth Popper

    (Medical University of Graz)

  • Myriam Johnson

    (Sir Mortimer B. Davis-Jewish General Hospital
    McGill University)

  • Leah Officer

    (University of Cambridge)

  • Ana Teodósio

    (University of Cambridge)

  • Massimo Broggini

    (Laboratory of Molecular Pharmacology IRCCS—Istituto di Ricerche Farmacologiche “Mario Negri”)

  • Koren K. Mann

    (Sir Mortimer B. Davis-Jewish General Hospital
    McGill University)

  • Maria Hatzoglou

    (Case Western Reserve University)

  • Ivan Topisirovic

    (Sir Mortimer B. Davis-Jewish General Hospital
    McGill University)

  • Ola Larsson

    (Karolinska Institute)

  • John Quesne

    (University of Leicester
    University of Cambridge
    Beatson Cancer Research Institute)

  • Antonis E. Koromilas

    (Sir Mortimer B. Davis-Jewish General Hospital
    McGill University)

Abstract

The integrated stress response (ISR) is an essential stress-support pathway increasingly recognized as a determinant of tumorigenesis. Here we demonstrate that ISR is pivotal in lung adenocarcinoma (LUAD) development, the most common histological type of lung cancer and a leading cause of cancer death worldwide. Increased phosphorylation of the translation initiation factor eIF2 (p-eIF2α), the focal point of ISR, is related to invasiveness, increased growth, and poor outcome in 928 LUAD patients. Dissection of ISR mechanisms in KRAS-driven lung tumorigenesis in mice demonstrated that p-eIF2α causes the translational repression of dual specificity phosphatase 6 (DUSP6), resulting in increased phosphorylation of the extracellular signal-regulated kinase (p-ERK). Treatments with ISR inhibitors, including a memory-enhancing drug with limited toxicity, provides a suitable therapeutic option for KRAS-driven lung cancer insofar as they substantially reduce tumor growth and prolong mouse survival. Our data provide a rationale for the implementation of ISR-based regimens in LUAD treatment.

Suggested Citation

  • Nour Ghaddar & Shuo Wang & Bethany Woodvine & Jothilatha Krishnamoorthy & Vincent Hoef & Cedric Darini & Urszula Kazimierczak & Nicolas Ah-son & Helmuth Popper & Myriam Johnson & Leah Officer & Ana Te, 2021. "The integrated stress response is tumorigenic and constitutes a therapeutic liability in KRAS-driven lung cancer," Nature Communications, Nature, vol. 12(1), pages 1-15, December.
    • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-24661-0
    DOI: 10.1038/s41467-021-24661-0
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