Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR TKIs) are first-line therapy for NSCLC. However, patients eventually deteriorate after inevitable acquisition of EGFR TKI-resistant mutations, which limits the long-term efficacy of EGFR-TKIs. Moreover, the majority of lung cancer patients who harboring wild-type EGFR achieve relatively little benefit from EGFR TKIs. Elevated wild-type EGFR expression not only participates in the pathogenesis and progression of lung cancer but also correlates with acquired resistance to third-generation EGFR TKIs. Therefore, it is urgent to identify a new EGFR-targeting therapeutic approach to circumvent EGFR TKIs resistance.
Figure 1. 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 progression. Targeting the TRIB3-EGFR interaction to promote EGFR degradation is a potential therapeutic option for the treatment of EGFR-related NSCLC.
On July 21, 2020, Dr. Zhuowei Hu's laboratory of State Key Laboratory of Bioactive Substance and Function of Natural Medicines published an article titled “TRIB3-EGFR interaction promotes lung cancer progression and defines a therapeutic target” online in Nature Communications.
In this study, Dr. Hu’s laboratory identified the pseudokinase Tribble 3 (TRIB3) was highly expressed in non-small cell lung cancer tissues and its expression positively correlates with EGFR expression. Lung cancer patients with higher expression of both EGFR and TRIB3 showed significant lower survival rate than patients with single or simultaneous low expression of EGFR and TRIB3. Mechanistically, TRIB3 interacts with EGFR and PKCα to form a heterotrimeric complex, which elicits EGFR recycling and promotes lung cancer progression. Disturbing the TRIB3-EGFR interaction with a stapled peptide attenuates NSCLC progression by accelerating EGFR degradation and sensitizes NSCLC cells to chemotherapeutic agents. This study not only uncovered the important role of abnormal wild-type EGFR in lung cancer progression, but also conducted a ‘‘proof of concept’’ study with a stapled peptide to confirm the TRIB3-EGFR interaction as a potential therapeutic target for lung cancer. These findings indicate that targeting EGFR degradation is a previously unappreciated therapeutic option in EGFR-related NSCLC.
Full text link:https://www.nature.com/articles/s41467-020-17385-0
