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Focal adhesion kinase-YAP signaling axis drives drug-tolerant persister cells and residual disease in lung cancer

Author

Listed:
  • Franziska Haderk

    (University of California, San Francisco
    University of California, San Francisco
    University of California, San Francisco)

  • Yu-Ting Chou

    (University of California, San Francisco
    University of California, San Francisco
    University of California, San Francisco)

  • Lauren Cech

    (University of California, San Francisco
    University of California, San Francisco)

  • Celia Fernández-Méndez

    (Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Instituto de Salud Carlos III (ISCIII))

  • Johnny Yu

    (University of California, San Francisco
    University of California, San Francisco
    University of California, San Francisco)

  • Victor Olivas

    (University of California, San Francisco
    University of California, San Francisco
    University of California, San Francisco)

  • Ismail M. Meraz

    (The University of Texas MD Anderson Cancer Center)

  • Dora Barbosa Rabago

    (University of California, San Francisco
    University of California, San Francisco
    University of California, San Francisco)

  • D. Lucas Kerr

    (University of California, San Francisco)

  • Carlos Gomez

    (University of California, San Francisco)

  • David V. Allegakoen

    (University of California, San Francisco
    University of California, San Francisco)

  • Juan Guan

    (University of California, San Francisco)

  • Khyati N. Shah

    (University of California, San Francisco
    University of California, San Francisco)

  • Kari A. Herrington

    (University of California, San Francisco)

  • Oghenekevwe M. Gbenedio

    (University of California, San Francisco)

  • Shigeki Nanjo

    (Kanazawa University)

  • Mourad Majidi

    (The University of Texas MD Anderson Cancer Center)

  • Whitney Tamaki

    (University of California, San Francisco)

  • Yashar K. Pourmoghadam

    (University of California, San Francisco)

  • Julia K. Rotow

    (Dana-Farber Cancer Institute)

  • Caroline E. McCoach

    (University of California, San Francisco
    University of California, San Francisco)

  • Jonathan W. Riess

    (University of California Davis Comprehensive Cancer Center)

  • J. Silvio Gutkind

    (University of California, San Diego)

  • Tracy T. Tang

    (Inc.)

  • Leonard Post

    (Inc.)

  • Bo Huang

    (University of California, San Francisco
    University of California, San Francisco
    Chan Zuckerberg Biohub)

  • Pilar Santisteban

    (Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Instituto de Salud Carlos III (ISCIII))

  • Hani Goodarzi

    (University of California, San Francisco
    University of California, San Francisco
    University of California, San Francisco)

  • Sourav Bandyopadhyay

    (University of California, San Francisco
    University of California, San Francisco)

  • Calvin J. Kuo

    (Stanford University School of Medicine)

  • Jeroen P. Roose

    (University of California, San Francisco)

  • Wei Wu

    (University of California, San Francisco)

  • Collin M. Blakely

    (University of California, San Francisco
    University of California, San Francisco)

  • Jack A. Roth

    (The University of Texas MD Anderson Cancer Center)

  • Trever G. Bivona

    (University of California, San Francisco
    University of California, San Francisco
    University of California, San Francisco)

Abstract

Targeted therapy is effective in many tumor types including lung cancer, the leading cause of cancer mortality. Paradigm defining examples are targeted therapies directed against non-small cell lung cancer (NSCLC) subtypes with oncogenic alterations in EGFR, ALK and KRAS. The success of targeted therapy is limited by drug-tolerant persister cells (DTPs) which withstand and adapt to treatment and comprise the residual disease state that is typical during treatment with clinical targeted therapies. Here, we integrate studies in patient-derived and immunocompetent lung cancer models and clinical specimens obtained from patients on targeted therapy to uncover a focal adhesion kinase (FAK)-YAP signaling axis that promotes residual disease during oncogenic EGFR-, ALK-, and KRAS-targeted therapies. FAK-YAP signaling inhibition combined with the primary targeted therapy suppressed residual drug-tolerant cells and enhanced tumor responses. This study unveils a FAK-YAP signaling module that promotes residual disease in lung cancer and mechanism-based therapeutic strategies to improve tumor response.

Suggested Citation

  • Franziska Haderk & Yu-Ting Chou & Lauren Cech & Celia Fernández-Méndez & Johnny Yu & Victor Olivas & Ismail M. Meraz & Dora Barbosa Rabago & D. Lucas Kerr & Carlos Gomez & David V. Allegakoen & Juan G, 2024. "Focal adhesion kinase-YAP signaling axis drives drug-tolerant persister cells and residual disease in lung cancer," Nature Communications, Nature, vol. 15(1), pages 1-19, December.
  • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-47423-0
    DOI: 10.1038/s41467-024-47423-0
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