Targeting the SYVN1-EGFR axis: a breakthrough strategy for TKI-resistant NSCLC

Non-small cell lung cancer (NSCLC) is the leading cause of cancer-related death. Currently, molecular targeted therapy remains a crucial approach to the treatment of NSCLC. However, the development of acquired drug resistance poses significant challenges for subsequent treatment. Identifying new therapeutic targets is of great significance for improving the prognosis of patients with NSCLC. Here, we verify synoviolin-1 (SYVN1) as a potential new therapeutic target for NSCLC. SYVN1 is highly expressed in NSCLC, and its upregulation is associated with poor prognosis. We show that the N-terminus (1-290 aa) of SYVN1 directly interacts with the intracellular domain of the epidermal growth factor receptor (EGFR) and activates EGFR signaling, promoting NSCLC growth in vitro and in vivo. Specifically, SYVN1 facilitates Lys 63-linked ubiquitination of EGFR and inhibits proteasome-mediated EGFR degradation. Moreover, we found that SYVN1 inhibits EGFR endocytosis, thereby increasing the amount of EGFR on the cell membrane. Furthermore, we confirmed that LS-102, an enzyme activity inhibitor of SYVN1, inhibits cell proliferation induced by SYVN1. Significantly, LS-102 in combination with the EGFR-TKI AZD9291 exhibits strong inhibitory effects on NSCLC growth and reverses the resistance of NSCLC to AZD9291. Together, our study demonstrates that the SYVN1-EGFR axis plays a critical role in NSCLC development and suggests that targeting the SYVN1-EGFR axis to destabilize EGFR may represent a putative therapeutic strategy for TKI-resistant NSCLC.