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
Affiliations
- Franziska Haderk
- Department of Medicine, University of California, San Francisco
- Yu-Ting Chou
- Department of Medicine, University of California, San Francisco
- Lauren Cech
- Department of Medicine, University of California, San Francisco
- Celia Fernández-Méndez
- Instituto de Investigaciones Biomédicas “Alberto Sols”, Consejo Superior de Investigaciones Científícas (CSIC) y Universidad Autónoma de Madrid (UAM), Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Instituto de Salud Carlos III (ISCIII)
- Johnny Yu
- Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco
- Victor Olivas
- Department of Medicine, University of California, San Francisco
- Ismail M. Meraz
- Department of Thoracic and Cardiovascular Surgery, The University of Texas MD Anderson Cancer Center
- Dora Barbosa Rabago
- Department of Medicine, University of California, San Francisco
- D. Lucas Kerr
- Department of Medicine, University of California, San Francisco
- Carlos Gomez
- Department of Medicine, University of California, San Francisco
- David V. Allegakoen
- Department of Medicine, University of California, San Francisco
- Juan Guan
- Department of Pharmaceutical Chemistry, University of California, San Francisco
- Khyati N. Shah
- Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco
- Kari A. Herrington
- Center for Advanced Light Microscopy, University of California, San Francisco
- Oghenekevwe M. Gbenedio
- Department of Anatomy, University of California, San Francisco
- Shigeki Nanjo
- Division of Medical Oncology, Cancer Research Institute, Kanazawa University
- Mourad Majidi
- Department of Thoracic and Cardiovascular Surgery, The University of Texas MD Anderson Cancer Center
- Whitney Tamaki
- Department of Medicine, University of California, San Francisco
- Yashar K. Pourmoghadam
- Department of Medicine, University of California, San Francisco
- Julia K. Rotow
- Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute
- Caroline E. McCoach
- Department of Medicine, University of California, San Francisco
- Jonathan W. Riess
- University of California Davis Comprehensive Cancer Center
- J. Silvio Gutkind
- Moores Cancer Center, University of California, San Diego
- Tracy T. Tang
- Vivace Therapeutics, Inc.
- Leonard Post
- Vivace Therapeutics, Inc.
- Bo Huang
- Department of Pharmaceutical Chemistry, University of California, San Francisco
- Pilar Santisteban
- Instituto de Investigaciones Biomédicas “Alberto Sols”, Consejo Superior de Investigaciones Científícas (CSIC) y Universidad Autónoma de Madrid (UAM), Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Instituto de Salud Carlos III (ISCIII)
- Hani Goodarzi
- Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco
- Sourav Bandyopadhyay
- Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco
- Calvin J. Kuo
- Department of Medicine, Division of Hematology, Stanford University School of Medicine
- Jeroen P. Roose
- Department of Anatomy, University of California, San Francisco
- Wei Wu
- Department of Medicine, University of California, San Francisco
- Collin M. Blakely
- Department of Medicine, University of California, San Francisco
- Jack A. Roth
- Department of Thoracic and Cardiovascular Surgery, The University of Texas MD Anderson Cancer Center
- Trever G. Bivona
- Department of Medicine, University of California, San Francisco
- DOI
- https://doi.org/10.1038/s41467-024-47423-0
- Journal volume & issue
-
Vol. 15,
no. 1
pp. 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.
