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<p>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.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年8月22日

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  • 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,
  • Luca Grumolato

摘要

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.