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Updated: Sep 9, 2025

Profiling Sensitivity to Targeted Therapies in EGFR-Mutant NSCLC Patient-Derived Organoids
Published on: November 22, 2021
Targeting the SYVN1-EGFR axis: a breakthrough strategy for TKI-resistant NSCLC
Xinsheng Xie1,2,3, Weilai Tong3,4, Yue Xie5
1Department of Orthopedic Surgery, The Third Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, China.
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.
Insights
Synoviolin-1 (SYVN1) promotes non-small cell lung cancer (NSCLC) growth by stabilizing EGFR. Targeting SYVN1 with LS-102 may overcome resistance to EGFR-TKIs like AZD9291 in NSCLC treatment.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Therapeutics
Background:
- Non-small cell lung cancer (NSCLC) is a leading cause of cancer mortality.
- Molecular targeted therapies are crucial for NSCLC treatment, but acquired drug resistance presents a major challenge.
- Identifying novel therapeutic targets is essential for improving patient outcomes in NSCLC.
Purpose of the Study:
- To investigate synoviolin-1 (SYVN1) as a potential therapeutic target in NSCLC.
- To elucidate the mechanism by which SYVN1 influences epidermal growth factor receptor (EGFR) signaling in NSCLC.
- To evaluate the therapeutic potential of targeting the SYVN1-EGFR axis, particularly in overcoming drug resistance.
Main Methods:
- Verification of SYVN1 expression and its correlation with prognosis in NSCLC.
- Investigation of the interaction between SYVN1 and EGFR, including ubiquitination and degradation pathways.
- Assessment of the efficacy of SYVN1 inhibitor LS-102, alone and in combination with EGFR-TKI AZD9291, on NSCLC growth in vitro and in vivo.
Main Results:
- SYVN1 is highly expressed in NSCLC and associated with poor prognosis.
- SYVN1 directly interacts with EGFR, promoting its Lys63-linked ubiquitination, inhibiting proteasomal degradation, and increasing cell membrane levels.
- LS-102 inhibits SYVN1-driven proliferation, and the combination of LS-102 and AZD9291 effectively inhibits NSCLC growth and overcomes AZD9291 resistance.
Conclusions:
- The SYVN1-EGFR axis plays a critical role in NSCLC development and progression.
- SYVN1 promotes NSCLC growth by stabilizing EGFR and enhancing its signaling.
- Targeting the SYVN1-EGFR axis to destabilize EGFR represents a promising therapeutic strategy for TKI-resistant NSCLC.
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