联合使用FGFR4抑制剂（H3B-6527）和奥沙利铂增强胃癌的抗肿瘤疗效

Background: Chemotherapy resistance continues to be a major obstacle in treating gastric cancer. This study investigates whether combining the FGFR4 inhibitor (H3B-6527) with Oxaliplatin can enhance treatment effectiveness in preclinical models, with emphasis on their combined impact on tumor growth inhibition and cell-death pathways. Material and Methods: To assess the effectiveness of the H3B-6527 and oxaliplatin combination, we utilized IC50 assays, colony formation tests, patient-derived xenograft (PDX) models, immunofluorescence, immunohistochemistry, western blotting and caspase-3/7 luminescence assays. These methods allowed us to evaluate how the combined treatment influences tumor cell proliferation, DNA damage, and apoptosis in gastric cancer cell lines (MKN28 and HGC27) as well as in tumor tissues. Results: IC50 analyses showed that both MKN28 and HGC27 cells were markedly more sensitive to the combination treatment than to either drug alone. Colony formation assays further demonstrated a substantial reduction in colony numbers with the combined therapy, underscoring its stronger anti-proliferative effect. In PDX mouse models, the combination produced significant tumor growth suppression and extended overall survival compared to controls. IF and IHC analyses revealed increased DNA damage, indicated by elevated gammaH2AX, decreased proliferation (Ki67), and higher apoptosis (cleaved caspase-3). Caspase-3/7 luminescence assays confirmed enhanced apoptotic activity in treated cells. Western blotting also showed increased cleaved PARP and gammaH2AX levels in both gastric cancer cell lines and PDX samples, supporting the heightened DNA damage and apoptosis triggered by the combined treatment. Conclusions: This study highlights the strong synergistic effect of H3B-6527 and oxaliplatin in inducing apoptosis, increasing DNA damage, and suppressing tumor growth in gastric cancer models. The results offer strong support for the potential clinical use of this combination as an effective treatment approach, particularly for gastric cancer patients who exhibit chemoresistance.