Circulating proteoglycan endocan mediates EGFR-driven progression of non-small cell lung cancer

Yi-Chieh Yang, Ke-Fan Pan, Wei-Jiunn Lee, Jer-Hwa Chang, Peng Tan, Chia-Chi Gu, Wei-Min Chang, Shun-Fa Yang, Michael Hsiao, Kuo-Tai Hua, Ming-Hsien Chien

Research output: Contribution to journalArticlepeer-review

8 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)3292-3304
Number of pages13
JournalCancer Research
Volume80
Issue number16
Early online dateJun 19 2020
DOIs
Publication statusPublished - Aug 15 2020

Keywords

  • Animals
  • Carcinoma, Non-Small-Cell Lung/genetics
  • Cell Line, Tumor
  • Cell Proliferation
  • Cell Survival
  • Disease Progression
  • Drug Resistance, Neoplasm/genetics
  • Epidermal Growth Factor/metabolism
  • ErbB Receptors/antagonists & inhibitors
  • Gene Expression
  • Genes, ras/genetics
  • Heterografts
  • Humans
  • Janus Kinases/metabolism
  • Lung Neoplasms/genetics
  • Lung/metabolism
  • MAP Kinase Signaling System
  • Mice
  • Mice, Inbred NOD
  • Mice, SCID
  • Mutation
  • Neoplasm Proteins/metabolism
  • Prognosis
  • Protein Kinase Inhibitors/pharmacology
  • Proteoglycans/antagonists & inhibitors
  • RNA, Messenger/metabolism
  • Receptor Cross-Talk
  • STAT3 Transcription Factor/metabolism
  • Up-Regulation
  • cdc25 Phosphatases/metabolism

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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