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:10.1038/s41467-024-47423-0

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

Nat Commun. 2024 May 3;15(1):3741. doi: 10.1038/s41467-024-47423-0.

Authors

Franziska Haderk^#^{1

2

3}, Yu-Ting Chou^#^{1

2

3}, Lauren Cech^#^{1

4}, Celia Fernández-Méndez⁵, Johnny Yu^{2

6

7}, Victor Olivas^{1

2

3}, Ismail M Meraz⁸, Dora Barbosa Rabago^{1

2

3}, D Lucas Kerr¹, Carlos Gomez¹, David V Allegakoen^{1

2}, Juan Guan⁴, Khyati N Shah^{2

9}, Kari A Herrington¹⁰, Oghenekevwe M Gbenedio¹¹, Shigeki Nanjo¹², Mourad Majidi⁸, Whitney Tamaki¹, Yashar K Pourmoghadam¹, Julia K Rotow¹³, Caroline E McCoach^{1

2}, Jonathan W Riess¹⁴, J Silvio Gutkind¹⁵, Tracy T Tang¹⁶, Leonard Post¹⁶, Bo Huang^{4

6

17}, Pilar Santisteban⁵, Hani Goodarzi^{2

6

7}, Sourav Bandyopadhyay^{2

9}, Calvin J Kuo¹⁸, Jeroen P Roose¹¹, Wei Wu¹, Collin M Blakely^{1

2}, Jack A Roth⁸, Trever G Bivona^{19

20

21}

Affiliations

¹ Department of Medicine, University of California, San Francisco, San Francisco, CA, USA.
² Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA, USA.
³ Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, CA, USA.
⁴ Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, CA, USA.
⁵ 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), Madrid, Spain.
⁶ Department of Biochemistry & Biophysics, University of California, San Francisco, San Francisco, CA, USA.
⁷ Department of Urology, University of California, San Francisco, San Francisco, CA, USA.
⁸ Department of Thoracic and Cardiovascular Surgery, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
⁹ Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, San Francisco, CA, USA.
¹⁰ Center for Advanced Light Microscopy, University of California, San Francisco, San Francisco, CA, USA.
¹¹ Department of Anatomy, University of California, San Francisco, San Francisco, CA, USA.
¹² Division of Medical Oncology, Cancer Research Institute, Kanazawa University, Kanazawa, Japan.
¹³ Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
¹⁴ University of California Davis Comprehensive Cancer Center, Sacramento, CA, USA.
¹⁵ Moores Cancer Center, University of California, San Diego, La Jolla, CA, USA.
¹⁶ Vivace Therapeutics, Inc., 1500 Fashion Island Blvd., Suite 102, San Mateo, CA, USA.
¹⁷ Chan Zuckerberg Biohub, San Francisco, CA, USA.
¹⁸ Department of Medicine, Division of Hematology, Stanford University School of Medicine, Stanford, CA, USA.
¹⁹ Department of Medicine, University of California, San Francisco, San Francisco, CA, USA. [email protected].
²⁰ Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA, USA. [email protected].
²¹ Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, CA, USA. [email protected].

^# Contributed equally.

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.

Publication types

Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural

MeSH terms

Adaptor Proteins, Signal Transducing / genetics
Adaptor Proteins, Signal Transducing / metabolism
Anaplastic Lymphoma Kinase / antagonists & inhibitors
Anaplastic Lymphoma Kinase / genetics
Anaplastic Lymphoma Kinase / metabolism
Animals
Antineoplastic Agents / pharmacology
Antineoplastic Agents / therapeutic use
Carcinoma, Non-Small-Cell Lung* / drug therapy
Carcinoma, Non-Small-Cell Lung* / genetics
Carcinoma, Non-Small-Cell Lung* / metabolism
Carcinoma, Non-Small-Cell Lung* / pathology
Cell Line, Tumor
Drug Resistance, Neoplasm* / genetics
ErbB Receptors / genetics
ErbB Receptors / metabolism
Focal Adhesion Kinase 1 / genetics
Focal Adhesion Kinase 1 / metabolism
Focal Adhesion Protein-Tyrosine Kinases / metabolism
Humans
Lung Neoplasms* / drug therapy
Lung Neoplasms* / genetics
Lung Neoplasms* / metabolism
Mice
Neoplasm, Residual
Proto-Oncogene Proteins p21(ras) / genetics
Proto-Oncogene Proteins p21(ras) / metabolism
Signal Transduction* / drug effects
Transcription Factors* / genetics
Transcription Factors* / metabolism
Xenograft Model Antitumor Assays
YAP-Signaling Proteins* / metabolism

Substances

Transcription Factors
YAP1 protein, human
YAP-Signaling Proteins
Adaptor Proteins, Signal Transducing
PTK2 protein, human
Focal Adhesion Kinase 1
ErbB Receptors
Anaplastic Lymphoma Kinase
Proto-Oncogene Proteins p21(ras)
EGFR protein, human
KRAS protein, human
ALK protein, human
Focal Adhesion Protein-Tyrosine Kinases
Antineoplastic Agents

Abstract

Publication types

MeSH terms

Substances

Grants and funding