# Epsin3 promotes non-small cell lung cancer progression via modulating EGFR stability

## TL;DR

Epsin3 helps lung cancer cells grow by keeping EGFR stable, which could lead to new treatments for drug-resistant cancer.

## Contribution

Epsin3's role in EGFR stabilization and NSCLC progression is newly identified, offering a potential therapeutic target.

## Key findings

- EPN3 expression is significantly up-regulated in NSCLC patients and correlates with shorter survival.
- EPN3 promotes EGFR recycling and prevents its degradation, sustaining cancer cell growth.
- EPN3's effect on EGFR remains unchanged even with TKI-resistant mutations.

## Abstract

The abnormal expression and overactivation of the epidermal growth factor receptor (EGFR), a typical cancer marker for non-small cell lung cancer (NSCLC), are closely related to the tumorigenesis and progression of NSCLC. However, the endocytosis mechanism of EGFR in lung cancer is not yet known. Epsin3 (EPN3), a member of the endocytic adaptor protein family, is essential for the endocytosis of multiple receptors. In this study, we aimed to investigate the role of EPN3 in modulating EGFR function, its effects on NSCLC progression, and its potential involvement in tyrosine kinase inhibitor (TKI) resistance, which remains a significant hurdle in NSCLC treatment.

Our findings revealed that the expression of EPN3 is significantly up-regulated in NSCLC patients. Elevated EPN3 expression was proportional to shorter overall survival in patients with NSCLC. Functional analyses revealed that EPN3 directly interacts with EGFR, enhancing its recycling to the plasma membrane and preventing its degradation via the lysosomal pathway. This stabilization of EGFR led to sustained downstream signalling, promoting NSCLC cell proliferation and migration. Notably, mutations in the EGFR tyrosine kinase domain, which typically confer resistance to TKIs, did not alter the regulatory effect of EPN3.

EPN3 enhances EGFR signalling by promoting its recycling and stability, contributing to NSCLC progression and TKI resistance. Targeting EPN3 could offer a novel therapeutic strategy to overcome drug resistance in EGFR-driven NSCLC.

The online version contains supplementary material available at 10.1186/s13578-025-01358-1.