Journal Article

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

Wurtz, Olivier, Dehedin, Julie, Chhouri, Houssein, Lee, Jiyoung, Kherrouche, Zoulika, Anouar, Youssef, Cartier, Dorthe, Godefroy, David, Guernet, Alexis, Bracquemond, David, Brunet, Lisa, Jamme, Philippe, Grumolato, Luca, Tulasne, David, Blanquer-Rosselló, Maria del Mar, Maraver, Antonio, Cho, Byoung Chul, Aaronson, Stuart A., Arena, Sabrina, Vinchent, Audrey, Alexandre, David, Goupil, Mathilde, Mancini, Maicol, Cheng, Chao, Duparc, Céline, Bérard, Caroline, Bardelli, Alberto, Li, Jian-Rong, Arabo, Arnaud, Coulouarn, Cédric, Yao, Shen, Cortot, Alexis B.

2025

Overview

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. The emergence of resistant subpopulations often underlies the development of resistance to cancer therapy. Here, using a DNA barcoding approach, the authors demonstrate EGFR TKI treatment in non-small cell lung cancer enriches for resistant subpopulation which can be prevented by treatment with the multikinase inhibitor sorafenib via inhibition of MKNK, STAT3 and MCL1.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 13 / 13/106 / 13/44 / 13/95 / 38 / 38/61 / 631/67/1059 / 631/67/1059/2326 / 631/67/1612/1350 / 64 / 64/60 / Animals / Cancer / Cancer therapies / 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 / Chemotherapy / Cloning / CRISPR / Deoxyribonucleic acid / DNA / DNA barcoding / Down-regulation / Drug Resistance, Neoplasm - drug effects / Drug Resistance, Neoplasm - genetics / Drugs / Epidermal growth factor receptors / ErbB Receptors - antagonists & inhibitors / ErbB Receptors - genetics / ErbB Receptors - metabolism / Experiments / Female / Gene sequencing / Growth factors / Humanities and Social Sciences / Humans / Immunological tolerance / Kinases / Life Sciences / Lung cancer / Lung Neoplasms - drug therapy / Lung Neoplasms - genetics / Lung Neoplasms - metabolism / Lung Neoplasms - pathology / MAP kinase / Mcl-1 protein / Mice / Mice, Nude / multidisciplinary / Mutation / Myeloid Cell Leukemia Sequence 1 Protein - genetics / Myeloid Cell Leukemia Sequence 1 Protein - metabolism / Non-small cell lung carcinoma / Phosphorylation / Phosphorylation - drug effects / Protein Kinase Inhibitors - pharmacology / Protein Kinase Inhibitors - therapeutic use / Science / Science (multidisciplinary) / Small cell lung carcinoma / Sorafenib - pharmacology / Stat3 protein / STAT3 Transcription Factor - metabolism / Subpopulations / Toxicity / Tumors / Tyrosine / Tyrosine kinase inhibitors / Xenograft Model Antitumor Assays / Xenotransplantation