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.
MethodsUsing 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.
ResultsSNCG 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.
ConclusionsSNCG 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.
AbbreviationsDLD-1-SNCGDLD-1 cells stably expressed SNCG
HCT116-BevHCT116 cells with acquired Bev-resistance
HCT116GKOHCT116 cells after SNCG knockout
HT29GKOHT29 cells after SNCG knockout
HUVECsHuman umbilical vein endothelial cells
LOVO-SNCGLOVO cells stably expressed SNCG
NOD/SCIDNon-obese diabetic/severe combined immunodeficiency
42#anti-SNCG monoclonal antibody
SPRsurface plasmon resonance
VEGFvascular endothelial growth factor
VEGFRvascular endothelial growth factor receptor
Keywordsgamma-synuclein (SNCG)
Bevacizumab resistance
angiogenesis
colorectal cancer (CRC)
VEGFR2
© 2025 The Author(s). Published by Elsevier Ltd.
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