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Discovery of a novel EGFR ligand DPBA that degrades EGFR and suppresses EGFR-positive NSCLC growth
Yao,Nan1,2; Wang,Chen Ran1,2; Liu,Ming Qun1; Li,Ying Jie1; Chen,Wei Min1; Li,Zheng Qiu1; Qi,Qi3; Lu,Jin Jian4; Fan,Chun Lin1,2; Chen,Min Feng1,2; Qi,Ming1,2; Li,Xiao Bo1,2; Hong,Jian3; Zhang,Dong Mei1,2; Ye,Wen Cai1,2
2020-12-01
Source PublicationSignal Transduction and Targeted Therapy
ISSN2095-9907
Volume5Issue:1
Abstract

Epidermal growth factor receptor (EGFR) activation plays a pivotal role in EGFR-driven non-small cell lung cancer (NSCLC) and is considered as a key target of molecular targeted therapy. EGFR tyrosine kinase inhibitors (TKIs) have been canonically used in NSCLC treatment. However, prevalent innate and acquired resistances and EGFR kinase-independent pro-survival properties limit the clinical efficacy of EGFR TKIs. Therefore, the discovery of novel EGFR degraders is a promising approach towards improving therapeutic efficacy and overcoming drug resistance. Here, we identified a 23-hydroxybetulinic acid derivative, namely DPBA, as a novel EGFR small-molecule ligand. It exerted potent in vitro and in vivo anticancer activity in both EGFR wild type and mutant NSCLC by degrading EGFR. Mechanistic studies disclosed that DPBA binds to the EGFR extracellular domain at sites differing from those of EGF and EGFR. DPBA did not induce EGFR dimerization, phosphorylation, and ubiquitination, but it significantly promoted EGFR degradation and repressed downstream survival pathways. Further analyses showed that DPBA induced clathrin-independent EGFR endocytosis mediated by flotillin-dependent lipid rafts and unaffected by EGFR TKIs. Activation of the early and late endosome markers rab5 and rab7 but not the recycling endosome marker rab11 was involved in DPBA-induced EGFR lysosomal degradation. The present study offers a new EGFR ligand for EGFR pharmacological degradation and proposes it as a potential treatment for EGFR-positive NSCLC, particularly NSCLC with innate or acquired EGFR TKI resistance. DPBA can also serve as a chemical probe in the studies on EGFR trafficking and degradation.

DOI10.1038/s41392-020-00251-2
URLView the original
Indexed BySCIE
WOS Research AreaBiochemistry & Molecular Biology ; Cell Biology
WOS SubjectBiochemistry & Molecular Biology ; Cell Biology
WOS IDWOS:000578258500001
Scopus ID2-s2.0-85092136704
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Cited Times [WOS]:4   [WOS Record]     [Related Records in WOS]
Document TypeJournal article
CollectionInstitute of Chinese Medical Sciences
Affiliation1.College of Pharmacy,Jinan University,Guangzhou,China
2.Guangdong Province Key Laboratory of Pharmacodynamic Constituents of Traditional Chinese Medicine and New Drugs Research,Jinan University,Guangzhou,China
3.School of Medicine,Jinan University,Guangzhou,China
4.State Key Laboratory of Quality Research in Chinese Medicine,Institute of Chinese Medical Sciences,University of Macau,Macao
Recommended Citation
GB/T 7714
Yao,Nan,Wang,Chen Ran,Liu,Ming Qun,et al. Discovery of a novel EGFR ligand DPBA that degrades EGFR and suppresses EGFR-positive NSCLC growth[J]. Signal Transduction and Targeted Therapy,2020,5(1).
APA Yao,Nan,Wang,Chen Ran,Liu,Ming Qun,Li,Ying Jie,Chen,Wei Min,Li,Zheng Qiu,Qi,Qi,Lu,Jin Jian,Fan,Chun Lin,Chen,Min Feng,Qi,Ming,Li,Xiao Bo,Hong,Jian,Zhang,Dong Mei,&Ye,Wen Cai.(2020).Discovery of a novel EGFR ligand DPBA that degrades EGFR and suppresses EGFR-positive NSCLC growth.Signal Transduction and Targeted Therapy,5(1).
MLA Yao,Nan,et al."Discovery of a novel EGFR ligand DPBA that degrades EGFR and suppresses EGFR-positive NSCLC growth".Signal Transduction and Targeted Therapy 5.1(2020).
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