SUPPLEMENTARY INFORMATION Supplementary material and methods, Table S1, and Figure S1-S7 - This file contains Supplementary material and methods; Table S1. The Cox univariate and multivariate analyses of endocan and clinicopathological factors in overall survival of patients in NSCLC patients.; Supplementary Figure S1. The clinical value of endocan in lung adenocarcinoma.; Supplementary Figure S2. Correlation of endocan and EGFR expression in lung cancer patients.; Supplementary Figure S3. Endocan enhances EGF�induced activation of EGFR in a concentration-dependent manner.; Supplementary Figure S4. The JAK/STAT3 and ERK/ELK signaling regulates endocan promoter activity.; Supplementary Figure S5. The interaction of endocan and EGF/EGFR complex.; Supplementary Figure S6. Endocan peptide treatment inhibits the PC9 tumor growth in vivo.; Supplementary Figure S7. Endocan peptide treatment suppresses the activation of EGFR harboring L858R/T790M/C797S triple mutations.
ARTICLE 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.
Endocan is a novel and critical regulator of EGF/EGFR signaling and serves as an alternative target of EGFR-TKI resistance in NSCLC.
