Prolonging lung cancer response to EGFR inhibition by targeting the selective advantage of resistant cells

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.

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Publication Details

Journal
Nature Communications
Published
2025-08-22
DOI
https://doi.org/10.1038/s41467-025-61788-w
Citations
1
Primary Topic
Lung Cancer Treatments and Mutations
Type
article
Field-Weighted Citation Impact
1.52

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article

Prolonging lung cancer response to EGFR inhibition by targeting the selective advantage of resistant cells

Philippe Jamme, Youssef Anouar, David Alexandre, Luca Grumolato et al.
1 citations
Nature Communications
Lung Cancer Treatments and Mutations
1.52
article

Prolonging lung cancer response to EGFR inhibition by targeting the selective advantage of resistant cells

Philippe Jamme, Youssef Anouar, David Alexandre, Luca Grumolato, Céline Duparc, Olivier Wurtz, Alexis B. Cortot, Dorthe Cartier, Sabrina Arena, Cédric Coulouarn, Alexis Guernet, Houssein Chhouri, Stuart A. Aaronson, Arnaud Arabo, Zoulika Kherrouche, Antonio Maraver, Alberto Bardelli, Byoung Chul Cho, David Tulasne, Maicol Mancini, Lisa J. Brunet, Audrey Vinchent, Chao Cheng, David Godefroy, Julie Dehedin, Ji‐Young Lee, Jiànróng Lǐ, Shen Yao, M. Gross Goupil, Caroline Bérard, Maria del Mar Blanquer-Rosselló, David Bracquemond
article en
1 citations

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.

Nature CommunicationsVol. 16(1)
Centre National de la Recherche Scientifique (FR), Inserm (FR), Baylor College of Medicine (US), Yonsei University (KR), Université de Montpellier (FR), Université de Lille (FR), Institut Pasteur de Lille (FR), Centre Hospitalier Universitaire de Lille (FR), Oncogenesis Stress Signaling (FR), Normandie Université (FR), Laboratoire d'Informatique, du Traitement de l'Information et des Systèmes (FR), IFOM (IT), Houston Institute for Clinical Research (US), Torino e-district (IT), Institut de Recherche en Cancérologie de Montpellier (FR), Institute for Research and Innovation in Biomedicine (FR), Candiolo Cancer Institute (IT), Istituti di Ricovero e Cura a Carattere Scientifico (IT), CANTHER - Hétérogénéité, Plasticité et Résistance aux Thérapies des Cancers (FR), University of Turin (IT), Université de Rennes (FR), Université de Rouen Normandie (FR), Icahn School of Medicine at Mount Sinai (US)
Vanderbilt University, University of Texas Southwestern Medical Center, European Commission, Agence Nationale de la Recherche, Institut National de la Santé et de la Recherche Médicale, Fondation pour la Recherche Médicale, Ministero della Salute, Fondation ARC pour la Recherche sur le Cancer, Ligue Contre le Cancer, Associazione Italiana per la Ricerca sul Cancro, Institut National Du Cancer, Université de Rouen, Ministry of Science and ICT, South Korea, Région Normandie
Openalex Percentile: Top 15%
Lung Cancer Treatments and Mutations
1.52
DOIOpen Access PDFOpenAlex
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