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

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.