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 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 PKC? 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.
Mesh Terms:
Adult, Animals, Antineoplastic Agents, Carcinoma, Non-Small-Cell Lung, Cell Cycle Proteins, Cell Line, Tumor, Disease Progression, Drug Resistance, Neoplasm, ErbB Receptors, Female, Humans, Kaplan-Meier Estimate, Lung Neoplasms, Male, Mice, Middle Aged, Mutation, Phosphorylation, Protein Kinase C-alpha, Protein Processing, Post-Translational, Protein Stability, Protein-Serine-Threonine Kinases, Proteolysis, Repressor Proteins, Survival Rate, Ubiquitination, Xenograft Model Antitumor Assays
Nat Commun
Date: Dec. 21, 2019
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