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 and Trever G. Bivona ()
Additional contact information
Franziska Haderk: University of California, San Francisco
Yu-Ting Chou: University of California, San Francisco
Lauren Cech: 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
Victor Olivas: University of California, San Francisco
Ismail M. Meraz: The University of Texas MD Anderson Cancer Center
Dora Barbosa Rabago: 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
Juan Guan: University of California, San Francisco
Khyati N. Shah: 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
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
Pilar Santisteban: Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Instituto de Salud Carlos III (ISCIII)
Hani Goodarzi: University of California, San Francisco
Sourav Bandyopadhyay: 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
Jack A. Roth: The University of Texas MD Anderson Cancer Center
Trever G. Bivona: University of California, San Francisco

Nature Communications, 2024, vol. 15, issue 1, 1-19

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-47423-0

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