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TRIB3-EGFR interaction promotes lung cancer progression and defines a therapeutic target

High expression or aberrant activation of epidermal growth factor receptor (EGFR) is related to tumor progression and therapy resistance across cancer types, including non-small cell lung cancer (NSCLC). EGFR tyrosine kinase inhibitors (TKIs) are first-line therapy for NSCLC. However, patients event...

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Detalles Bibliográficos
Autores principales: Yu, Jiao-jiao, Zhou, Dan-dan, Yang, Xiao-xiao, Cui, Bing, Tan, Feng-wei, Wang, Junjian, Li, Ke, Shang, Shuang, Zhang, Cheng, Lv, Xiao-xi, Zhang, Xiao-wei, Liu, Shan-shan, Yu, Jin-mei, Wang, Feng, Huang, Bo, Hua, Fang, Hu, Zhuo-Wei
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7374170/
https://www.ncbi.nlm.nih.gov/pubmed/32694521
http://dx.doi.org/10.1038/s41467-020-17385-0
Descripción
Sumario:High expression or aberrant activation of epidermal growth factor receptor (EGFR) is related to tumor progression and therapy resistance across cancer types, including non-small cell lung cancer (NSCLC). EGFR tyrosine kinase inhibitors (TKIs) are first-line therapy for NSCLC. However, patients eventually deteriorate after inevitable acquisition of EGFR TKI-resistant mutations, highlighting the need for therapeutics with alternative mechanisms of action. Here, we report that the elevated tribbles pseudokinase 3 (TRIB3) is positively associated with EGFR stability and NSCLC progression. TRIB3 interacts with EGFR and recruits PKCα to induce a Thr654 phosphorylation and WWP1-induced Lys689 ubiquitination in the EGFR juxtamembrane region, which enhances EGFR recycling, stability, downstream activity, and NSCLC stemness. Disturbing the TRIB3-EGFR interaction with a stapled peptide attenuates NSCLC progression by accelerating EGFR degradation and sensitizes NSCLC cells to chemotherapeutic agents. These findings indicate that targeting EGFR degradation is a previously unappreciated therapeutic option in EGFR-related NSCLC.