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

Lisa Brunet, David Alexandre, Jiyoung Lee, Maria del Mar Blanquer-Rosselló, David Bracquemond, Alexis Guernet, Houssein Chhouri, Mathilde Goupil, Zoulika Kherrouche, Arnaud Arabo, Maicol Mancini, Dorthe Cartier, Shen Yao, David Godefroy, Julie Dehedin, Jian-Rong Li, Céline Duparc, Philippe Jamme, Audrey Vinchent, Caroline Bérard, David Tulasne, Sabrina Arena, Alberto Bardelli, Chao Cheng, Byoung Chul Cho, Olivier Wurtz, Cédric Coulouarn, Antonio Maraver, Stuart A. Aaronson, Alexis B. Cortot, Youssef Anouar and Luca Grumolato ()
Additional contact information
Lisa Brunet: Univ Rouen Normandie, INSERM NorDiC UMR 1239
David Alexandre: Univ Rouen Normandie, INSERM NorDiC UMR 1239
Jiyoung Lee: Univ Rouen Normandie, INSERM NorDiC UMR 1239
Maria del Mar Blanquer-Rosselló: Univ Rouen Normandie, INSERM NorDiC UMR 1239
David Bracquemond: Institut Régional du Cancer de Montpellier (ICM)
Alexis Guernet: Univ Rouen Normandie, INSERM NorDiC UMR 1239
Houssein Chhouri: Univ Rouen Normandie, INSERM NorDiC UMR 1239
Mathilde Goupil: Univ Rouen Normandie, INSERM NorDiC UMR 1239
Zoulika Kherrouche: Plasticity and Resistance to Therapies
Arnaud Arabo: Univ Rouen Normandie, INSERM, CNRS, Normandie Université, HeRacLeS US51 UAR2026 SRB
Maicol Mancini: Institut Régional du Cancer de Montpellier (ICM)
Dorthe Cartier: Univ Rouen Normandie, INSERM NorDiC UMR 1239
Shen Yao: Icahn School of Medicine at Mount Sinai
David Godefroy: Univ Rouen Normandie, INSERM NorDiC UMR 1239
Julie Dehedin: Univ Rouen Normandie, INSERM NorDiC UMR 1239
Jian-Rong Li: Baylor College of Medicine
Céline Duparc: Univ Rouen Normandie, INSERM NorDiC UMR 1239
Philippe Jamme: Plasticity and Resistance to Therapies
Audrey Vinchent: Plasticity and Resistance to Therapies
Caroline Bérard: Univ Rouen Normandie, LITIS EA 4108
David Tulasne: Plasticity and Resistance to Therapies
Sabrina Arena: University of Torino
Alberto Bardelli: University of Torino
Chao Cheng: Baylor College of Medicine
Byoung Chul Cho: Yonsei University College of Medicine
Olivier Wurtz: Univ Rouen Normandie, INSERM, U1245, Cancer and Brain Genomics
Cédric Coulouarn: Centre de Lutte contre le Cancer Eugène Marquis
Antonio Maraver: Institut Régional du Cancer de Montpellier (ICM)
Stuart A. Aaronson: Icahn School of Medicine at Mount Sinai
Alexis B. Cortot: Plasticity and Resistance to Therapies
Youssef Anouar: Univ Rouen Normandie, INSERM NorDiC UMR 1239
Luca Grumolato: Univ Rouen Normandie, INSERM NorDiC UMR 1239

Nature Communications, 2025, vol. 16, issue 1, 1-23

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41467-025-61788-w

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