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Circulating Proteoglycan Endocan Mediates EGFR-Driven Progression of Non–Small Cell Lung Cancer
- Source :
- Cancer Research. 80:3292-3304
- Publication Year :
- 2020
- Publisher :
- American Association for Cancer Research (AACR), 2020.
-
Abstract
- Although new generations of EGFR-tyrosine kinase inhibitors (EGFR-TKI) have been developed for the treatment of patients with non–small cell lung cancer (NSCLC) with EGFR-mutant tumors, TKI resistance often returns as a result of additional EGFR mutations. In addition to seeking for next-generation EGFR-TKI, developing novel EGFR-targeting strategies may hold the key to overcome the vicious cycle of TKI resistance. Endocan is known as a receptor tyrosine kinase ligand enhancer in tumorigenesis, but the impact of endocan on EGFR-driven NSCLC progression remains unknown. In this study, higher endocan levels were found in lung tumors compared with cancer-free tissues and correlated with poor prognosis in patients with NSCLC harboring mutant EGFR; circulating endocan levels were also significantly higher in patients with mutant EGFR. Endocan facilitated EGFR signaling via direct binding and enhancing of the EGF–EGFR interaction and supported the growth of tumors driven by mutated EGFR. Activated EGFR in turn upregulated expression of endocan via JAK/STAT3 and ERK/ELK cascades, thus forming a positive regulatory loop of endocan-EGFR signaling. On the basis of the binding region between endocan and EGFR, we designed therapeutic peptides and demonstrated promising therapeutic effects in xenografts harboring EGFR mutations including TKI-resistant T790M. Together, our findings highlight the novel interaction between endocan and EGFR and new opportunities to effectively target endocan-EGFR regulatory axis in patients with TKI-resistant NSCLC. Significance: Endocan is a novel and critical regulator of EGF/EGFR signaling and serves as an alternative target of EGFR-TKI resistance in NSCLC.
- Subjects :
- 0301 basic medicine
MAPK/ERK pathway
Cancer Research
Lung Neoplasms
Gene Expression
Mice, SCID
medicine.disease_cause
Receptor tyrosine kinase
Mice
T790M
0302 clinical medicine
Mice, Inbred NOD
Carcinoma, Non-Small-Cell Lung
STAT3
Lung
biology
Kinase
Prognosis
Neoplasm Proteins
Up-Regulation
ErbB Receptors
Oncology
030220 oncology & carcinogenesis
Disease Progression
Heterografts
Proteoglycans
STAT3 Transcription Factor
Cell Survival
MAP Kinase Signaling System
03 medical and health sciences
Downregulation and upregulation
Cell Line, Tumor
medicine
Animals
Humans
cdc25 Phosphatases
RNA, Messenger
Lung cancer
Protein Kinase Inhibitors
Cell Proliferation
Janus Kinases
Epidermal Growth Factor
business.industry
Receptor Cross-Talk
medicine.disease
respiratory tract diseases
Genes, ras
030104 developmental biology
Drug Resistance, Neoplasm
Mutation
biology.protein
Cancer research
business
Carcinogenesis
Subjects
Details
- ISSN :
- 15387445 and 00085472
- Volume :
- 80
- Database :
- OpenAIRE
- Journal :
- Cancer Research
- Accession number :
- edsair.doi.dedup.....966f70bdc1a5154f82a32fc24f4bb7ea