期刊
NATURE COMMUNICATIONS
卷 11, 期 1, 页码 -出版社
NATURE PORTFOLIO
DOI: 10.1038/s41467-020-17385-0
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资金
- National Key R&D Program of China [2017YFA0205400]
- National Natural Science Foundation of China [81773781, 81530093, 81472717, 81673474, 81973344, 81400140, 81703564]
- Beijing Natural Science Foundation [7162133]
- CAMS Innovation Found for Medical Sciences [2016-I2M-1-007, 2019-I2M-1-005, 2016-I2M-3-008, 2016-I2M-1-011]
- Beijing Outstanding Young Scientist Program [BJJWZYJH01201910023028]
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 PKCa 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.
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