Yang Y.-C.Pan K.-F.Lee W.-J.Chang J.-H.Tan P.Gu C.-C.Chang W.-M.Yang S.-F.Hsiao M.KUO-TAI HUAChien M.-H.2021-05-272021-05-2720200008-5472https://www.scopus.com/inward/record.uri?eid=2-s2.0-85089787860&doi=10.1158%2f0008-5472.CAN-20-0005&partnerID=40&md5=edc30b0d140e7c52bcfeeda556f602d4https://scholars.lib.ntu.edu.tw/handle/123456789/563146Although 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. ? 2020 American Association for Cancer Research.[SDGs]SDG3biological marker; Cdc25A phosphatase; endocan; epidermal growth factor; epidermal growth factor receptor; mitogen activated protein kinase; mutant protein; protein tyrosine kinase inhibitor; protein tyrosine phosphatase; proteoglycan; small interfering RNA; STAT3 protein; transcription factor; transcription factor Elk; unclassified drug; Article; cancer growth; cancer prognosis; cancer resistance; controlled study; disease association; drug protein binding; drug targeting; EGF gene; EGFR gene; endocan EGFR signaling; ERK ELK signaling; human; human cell; human tissue; in vitro study; in vivo study; JAK-STAT signaling; JAK-STAT3 signaling; lung carcinogenesis; non small cell lung cancer; priority journal; protein protein interaction; upregulationjournal article10.1158/0008-5472.CAN-20-0005325615332-s2.0-85089787860