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

Jiao-Jiao Yu,Shan-Shan Liu,Feng Wang,Cheng Zhang,Zhuo-Wei Hu,Dan-Dan Zhou,Xiao-Xi Lv,Shuang Shang,Bo Huang,Ke Li,Xiao-Wei Zhang,Feng-Wei Tan,Fang Hua,Junjian Wang,Xiao-Xiao Yang,Bing Cui,Jin-Mei Yu

doi:10.1038/s41467-020-17385-0

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.

Highlights

1, Feng-wei Tan[3], Junjian Wang[4], Ke Li5, 1, Shan-shan Liu[1], Jin-mei Yu 1, Feng Wang[1], 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)
As tribbles pseudokinase 3 (TRIB3) was reported to connect with NSCLC progression or response to therapeutic agents with some controversial opinions[41,42,43,44,45], we evaluated the genetic depletion of TRIB3 on NSCLC progression
Targeted EGFR therapeutics such as tyrosine kinase inhibitors (TKIs) are largely effective in the treatment of NSCLC with mutated EGFR, the development of resistance is a challenging issue for using TKI therapies in these patients[3]

Summary

Introduction

1, Feng-wei Tan[3], Junjian Wang[4], Ke Li5, 1, Shan-shan Liu[1], Jin-mei Yu 1, Feng Wang[1], 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). 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. Three generations of EGFR TKIs have been developed to reversibly (the first generation) or irreversibly (the second- and the third generation) inhibit EGFR tyrosine kinase activity and are widely used in NSCLC treatment. Elevated WT-EGFR expression correlates with acquired resistance to third-generation EGFR

Methods

Results

Conclusion