Prolonging lung cancer response to EGFR inhibition by targeting the selective advantage of resistant cells
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.
Article Details
Authors (32)
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
State Key Laboratory of Materials Low-Carbon Recycling
Céline Duparc
Philippe Jamme
Audrey Vinchent
Caroline Bérard
David Tulasne
Sabrina Arena
Alberto Bardelli
Chao Cheng
School of Life Sciences, Key Laboratory of Pesticide and Chemical Biology of Ministry of Education, and Hubei Key Laboratory of Genetic Regulation and Integrative Biology, Central China Normal University
Byoung Chul Cho
Olivier Wurtz
Cédric Coulouarn
Antonio Maraver
Stuart A. Aaronson
Alexis B. Cortot
Youssef Anouar
Luca Grumolato