2. Academic Validation
  3. Targeting the SYVN1-EGFR axis: a breakthrough strategy for TKI-resistant NSCLC

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

  • Cell Death Dis. 2025 Aug 28;16(1):655. doi: 10.1038/s41419-025-07978-2.
Xinsheng Xie # 1 2 3,  Weilai Tong # 3 4,  Yue Xie # 5,  Haoxin Jiang # 3 4,  Alan Jiang 3,  Junming Huang 3 4,  Zhili Liu 6 7 8,  Jingjing Yu 9
Affiliations

Affiliations

  • 1 Department of Orthopedic Surgery, The Third Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, China.
  • 2 School of Information Management, Jiangxi University of Finance and Economics, Nanchang, China.
  • 3 Jiangxi Provincial Key Laboratory of Spine and Spinal Cord Diseases, Nanchang, China.
  • 4 Department of Orthopedic Surgery, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, China.
  • 5 Department of Urology, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, China.
  • 6 Department of Orthopedic Surgery, The Third Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, China. zhili-liu@ncu.edu.cn.
  • 7 Jiangxi Provincial Key Laboratory of Spine and Spinal Cord Diseases, Nanchang, China. zhili-liu@ncu.edu.cn.
  • 8 Department of Orthopedic Surgery, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, China. zhili-liu@ncu.edu.cn.
  • 9 Department of Respiratory and Critical Care Medicine, Jiangxi Provincial Key Laboratory of Respiratory Diseases, Jiangxi Institute of Respiratory Diseases, Jiangxi Clinical Research Center for Respiratory Diseases, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, China. ndyfy01237@ncu.edu.cn.
  • # Contributed equally.
PMID: 40877231 DOI: 10.1038/s41419-025-07978-2
Abstract

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.

Figures
Products
Inhibitors & Agonists