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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Adult
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Animals
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Antineoplastic Agents / pharmacology*
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Antineoplastic Agents / therapeutic use
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Carcinoma, Non-Small-Cell Lung / drug therapy
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Carcinoma, Non-Small-Cell Lung / genetics
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Carcinoma, Non-Small-Cell Lung / mortality
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Carcinoma, Non-Small-Cell Lung / pathology*
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Cell Cycle Proteins / metabolism*
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Cell Line, Tumor
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Disease Progression
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Drug Resistance, Neoplasm / drug effects
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Drug Resistance, Neoplasm / genetics
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ErbB Receptors / antagonists & inhibitors
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ErbB Receptors / genetics
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ErbB Receptors / metabolism
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Female
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Humans
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Kaplan-Meier Estimate
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Lung Neoplasms / drug therapy
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Lung Neoplasms / genetics
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Lung Neoplasms / mortality
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Lung Neoplasms / pathology*
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Male
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Mice
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Middle Aged
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Mutation
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Phosphorylation / drug effects
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Protein Kinase C-alpha / metabolism
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Protein Processing, Post-Translational / drug effects
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Protein Serine-Threonine Kinases / antagonists & inhibitors*
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Protein Serine-Threonine Kinases / metabolism
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Protein Stability / drug effects
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Proteolysis / drug effects
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Repressor Proteins / metabolism*
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Survival Rate
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Ubiquitination / drug effects
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Xenograft Model Antitumor Assays
Substances
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Antineoplastic Agents
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Cell Cycle Proteins
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Repressor Proteins
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TRIB3 protein, human
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EGFR protein, human
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ErbB Receptors
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Protein Serine-Threonine Kinases
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PRKCA protein, human
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Protein Kinase C-alpha