Circulating Proteoglycan Endocan Mediates EGFR-Driven Progression of Non–Small Cell Lung Cancer

Jun 21, 2020Cancer research

Blood Protein Endocan May Help Growth of Non-Small Cell Lung Cancer Driven by EGFR

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Abstract

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.

Endocan levels are significantly elevated in patients with non-small cell lung cancer (NSCLC) that have mutant EGFR compared to healthy tissue.
Circulating endocan levels are also higher in patients with mutant EGFR, indicating a systemic association with the disease.
Endocan enhances EGFR signaling by directly binding to it and boosting the interaction between EGF and EGFR, which supports tumor growth.
Activated EGFR increases the expression of endocan through specific cellular signaling pathways, creating a positive feedback loop.
Therapeutic peptides targeting the interaction between endocan and EGFR show promising effects in tumor models with TKI-resistant mutations.

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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.

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Circulating Proteoglycan Endocan Mediates EGFR-Driven Progression of Non–Small Cell Lung Cancer

Abstract

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