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

Jiao-jiao Yu, Dan-dan Zhou, Xiao-xiao Yang, Bing Cui, Feng-wei Tan, Junjian Wang, Ke Li, Shuang Shang, Cheng Zhang, Xiao-xi Lv, Xiao-wei Zhang, Shan-shan Liu, Jin-mei Yu, Feng Wang, Bo Huang, Fang Hua () and Zhuo-Wei Hu ()
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Jiao-jiao Yu: Chinese Academy of Medical Sciences & Peking Union Medical College
Dan-dan Zhou: Chinese Academy of Medical Sciences & Peking Union Medical College
Xiao-xiao Yang: Chinese Academy of Medical Sciences & Peking Union Medical College
Bing Cui: Chinese Academy of Medical Sciences & Peking Union Medical College
Feng-wei Tan: Chinese Academy of Medical Sciences & Peking Union Medical College
Junjian Wang: Sun Yat-sen University
Ke Li: Chinese Academy of Medical Sciences & Peking Union Medical College
Shuang Shang: Chinese Academy of Medical Sciences & Peking Union Medical College
Cheng Zhang: Chinese Academy of Medical Sciences & Peking Union Medical College
Xiao-xi Lv: Chinese Academy of Medical Sciences & Peking Union Medical College
Xiao-wei Zhang: Chinese Academy of Medical Sciences & Peking Union Medical College
Shan-shan Liu: Chinese Academy of Medical Sciences & Peking Union Medical College
Jin-mei Yu: Chinese Academy of Medical Sciences & Peking Union Medical College
Feng Wang: Chinese Academy of Medical Sciences & Peking Union Medical College
Bo Huang: Chinese Academy of Medical Sciences & Peking Union Medical College
Fang Hua: Chinese Academy of Medical Sciences & Peking Union Medical College
Zhuo-Wei Hu: Chinese Academy of Medical Sciences & Peking Union Medical College

Nature Communications, 2020, vol. 11, issue 1, 1-16

Abstract: Abstract 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.

Date: 2020
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DOI: 10.1038/s41467-020-17385-0

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