2. Academic Validation
  3. Gamma-synuclein drives bevacizumab resistance in colorectal cancer via VEGFR2 activation and angiogenesis

Gamma-synuclein drives bevacizumab resistance in colorectal cancer via VEGFR2 activation and angiogenesis

  • Drug Resist Updat. 2025 Sep 9:84:101299. doi: 10.1016/j.drup.2025.101299.
Caiyun Liu 1,  Lin Meng 2,  Lixin Wang 2,  Bin Dong 3,  Like Qu 4,  Chuanke Zhao 5,  Chengchao Shou 6
Affiliations

Affiliations

  • 1 Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Biochemistry & Molecular Biology, Peking University Cancer Hospital & Institute, No.52 Fucheng Road, Haidian District, Beijing 100142, China. Electronic address: liucaiyun@pku.edu.cn.
  • 2 Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Biochemistry & Molecular Biology, Peking University Cancer Hospital & Institute, No.52 Fucheng Road, Haidian District, Beijing 100142, China.
  • 3 Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Central Laboratory, Peking University Cancer Hospital & Institute, No.52 Fucheng Road, Haidian District, Beijing 100142, China.
  • 4 Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Biochemistry & Molecular Biology, Peking University Cancer Hospital & Institute, No.52 Fucheng Road, Haidian District, Beijing 100142, China. Electronic address: qulike@pku.edu.cn.
  • 5 Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Biochemistry & Molecular Biology, Peking University Cancer Hospital & Institute, No.52 Fucheng Road, Haidian District, Beijing 100142, China. Electronic address: zhaochk@bjmu.edu.cn.
  • 6 Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Biochemistry & Molecular Biology, Peking University Cancer Hospital & Institute, No.52 Fucheng Road, Haidian District, Beijing 100142, China. Electronic address: cshou@vip.sina.com.
PMID: 40939487 DOI: 10.1016/j.drup.2025.101299
Abstract

Background: Resistance to Bevacizumab (Bev) remains a major obstacle in colorectal Cancer (CRC) treatment. Gamma-synuclein (SNCG), overexpressed in tumor vasculature and Cancer cells, is investigated here for its role in Bev resistance and therapeutic potential.

Methods: Using isogenic CRC models with SNCG overexpression or knockout, we assessed SNCG's impact on Bev response in vitro and in vivo. The therapeutic efficacy of combining Bev with an anti-SNCG monoclonal antibody (42#) was evaluated in Bev-resistant models. Mechanistic studies, including ELISA, Western blot, surface plasmon resonance (SPR), and molecular docking, explored interactions between SNCG, VEGF, and VEGFR2.

Results: SNCG overexpression reduced Bev sensitivity by impairing the inhibition of migration, invasion, and spheroid formation, whereas SNCG knockout enhanced therapeutic response. Molecular docking revealed that SNCG binds VEGFR2 at an allosteric site, forming a stable ternary complex (SNCG-VEGF-VEGFR2) with enhanced hydrogen bonding, which sustained VEGFR2 phosphorylation and angiogenesis. In vivo, SNCG-overexpressing tumors showed reduced responsiveness to Bev (42.8 % inhibition vs. 64.3 % in controls, p < 0.05), while SNCG-deficient tumors exhibited a 3.2-fold increase in sensitivity. Combining Bev with 42# synergistically suppressed tumor growth (0.70 ± 0.36 g vs. 1.55 ± 0.41 g, p = 0.003), reduced metastatic burden (0.29 ± 0.23 g vs. 0.97 ± 0.42 g, p = 0.006), and extended median survival (86.8 vs. 69.8 days, p = 0.033) in Bev-resistant models.

Conclusions: SNCG drives Bev resistance in CRC by forming a ternary complex with VEGF and VEGFR2, enhancing VEGFR2 signaling and angiogenesis. Dual targeting of VEGF and SNCG represents a promising therapeutic strategy to overcome Bev resistance, with the potential to improve outcomes in CRC patients.

Keywords

Bevacizumab resistance; VEGFR2; angiogenesis; colorectal cancer (CRC); gamma-synuclein (SNCG).

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