Faculty, Staff and Student Publications
Publication Date
5-3-2024
Journal
Nature Communications
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.
Keywords
Humans, Lung Neoplasms, Signal Transduction, Transcription Factors, Carcinoma, Non-Small-Cell Lung, YAP-Signaling Proteins, Cell Line, Tumor, Animals, Drug Resistance, Neoplasm, Adaptor Proteins, Signal Transducing, Neoplasm, Residual, Mice, Focal Adhesion Kinase 1, ErbB Receptors, Anaplastic Lymphoma Kinase, Proto-Oncogene Proteins p21(ras), Focal Adhesion Protein-Tyrosine Kinases, Antineoplastic Agents, Xenograft Model Antitumor Assays, Non-small-cell lung cancer, Cancer therapeutic resistance
DOI
10.1038/s41467-024-47423-0
PMID
38702301
PMCID
PMC11068778
PubMedCentral® Posted Date
5-3-2024
PubMedCentral® Full Text Version
Post-print
Published Open-Access
yes
Included in
Bioinformatics Commons, Biomedical Informatics Commons, Genetic Phenomena Commons, Medical Genetics Commons, Neoplasms Commons, Oncology Commons
