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

研究成果: 雜誌貢獻文章

摘要

Although new generations of EGFR-tyrosine kinase inhibitors (EGFR-TKI) have been developed for the treatment of non-small cell lung cancer (NSCLC) patients 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 NSCLC patients 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. Based on 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 TKI-resistant NSCLC patients.
原文英語
期刊Cancer Research
DOIs
出版狀態打印前電子出版 - 六月 19 2020

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