Nature Communications (May 2024)

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

  • 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 Guan,
  • Khyati N. Shah,
  • Kari A. Herrington,
  • Oghenekevwe M. Gbenedio,
  • Shigeki Nanjo,
  • Mourad Majidi,
  • Whitney Tamaki,
  • Yashar K. Pourmoghadam,
  • Julia K. Rotow,
  • Caroline E. McCoach,
  • Jonathan W. Riess,
  • J. Silvio Gutkind,
  • Tracy T. Tang,
  • Leonard Post,
  • Bo Huang,
  • Pilar Santisteban,
  • Hani Goodarzi,
  • Sourav Bandyopadhyay,
  • Calvin J. Kuo,
  • Jeroen P. Roose,
  • Wei Wu,
  • Collin M. Blakely,
  • Jack A. Roth,
  • Trever G. Bivona

DOI
https://doi.org/10.1038/s41467-024-47423-0
Journal volume & issue
Vol. 15, no. 1
pp. 1 – 19

Abstract

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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.