Language
English
Publication Date
8-22-2025
Journal
Nature Communications
DOI
10.1038/s41467-025-61788-w
PMID
40846697
PMCID
PMC12373916
PubMedCentral® Posted Date
8-22-2025
PubMedCentral® Full Text Version
Post-print
Abstract
Non-small cell lung cancers (NSCLCs) treated with tyrosine kinase inhibitors (TKIs) of the epidermal growth factor receptor (EGFR) almost invariably relapse in the long term, due to the emergence of subpopulations of resistant cells. Through a DNA barcoding approach, we show that the clinically approved drug sorafenib specifically abolishes the selective advantage of EGFR-TKI-resistant cells, while preserving the response of EGFR-TKI-sensitive cells. Sorafenib is active against multiple mechanisms of resistance/tolerance to EGFR-TKIs and its effects depend on early inhibition of MAPK-interacting kinase (MKNK) activity and signal transducer and activator of transcription 3 (STAT3) phosphorylation, and later down-regulation of MCL1 and EGFR. Using different xenograft and allograft models, we show that the sorafenib-EGFR-TKI combination can delay tumor growth and promote the recruitment of inflammatory cells. Together, our findings indicate that sorafenib can prolong the response to EGFR-TKIs by targeting NSCLC capacity to adapt to treatment through the emergence of resistant cells.
Keywords
Humans, Drug Resistance, Neoplasm, Lung Neoplasms, ErbB Receptors, Sorafenib, Animals, Carcinoma, Non-Small-Cell Lung, Protein Kinase Inhibitors, Xenograft Model Antitumor Assays, Cell Line, Tumor, Mice, STAT3 Transcription Factor, Myeloid Cell Leukemia Sequence 1 Protein, Phosphorylation, Female, Mice, Nude, Non-small-cell lung cancer, Cancer therapeutic resistance, Cancer therapy
Published Open-Access
yes
Recommended Citation
Brunet, Lisa; Alexandre, David; Lee, Jiyoung; et al., "Prolonging Lung Cancer Response to Egfr Inhibition by Targeting the Selective Advantage of Resistant Cells" (2025). Faculty, Staff and Students Publications. 6228.
https://digitalcommons.library.tmc.edu/baylor_docs/6228