Abstract 1672: Synergistic efficacy of FGFR4 inhibitor (H3B-6527) and oxaliplatin combination therapy in gastric cancer models

Abstract Background: Resistance to chemotherapy remains a significant challenge in the treatment of gastric cancer. This study evaluates the therapeutic potential of a combination of the FGFR4 inhibitor H3B-6527 and Oxaliplatin in preclinical models, focusing on their synergistic effects on tumor suppression and cell death mechanisms. Material and Methods: To evaluate the efficacy of H3B-6527 and oxaliplatin combination, we employed IC50 analyses, colony formation assays, patient-derived xenograft (PDX) models, immunofluorescence (IF), immunohistochemistry (IHC), western blotting, and caspase-3/7 luminescence assays. These techniques were used to assess the impact of the drug combination on tumor cell proliferation, DNA damage, and apoptosis in gastric cancer cell lines (MKN28 and HGC27) and tumor tissues. Results: IC50 analyses demonstrated significantly enhanced sensitivity to the combination therapy in both MKN28 and HGC27 cell lines compared to either agent alone. Colony formation assays revealed that the combination therapy drastically reduced colony counts relative to monotherapies, highlighting its superior anti-proliferative effects. In PDX mouse models, the combination therapy led to pronounced tumor growth inhibition and significantly prolonged survival compared to controls. IF and IHC analyses showed marked increases in DNA damage, as evidenced by γH2AX expression, along with reduced proliferation (Ki67) and elevated apoptosis (cleaved caspase-3). Caspase-3/7 luminescence assays confirmed heightened apoptotic activity in treated cell lines. Western blot analysis revealed elevated levels of cleaved PARP and γH2AX in both gastric cancer cell lines and PDX tissues, corroborating the enhanced DNA damage and apoptotic response induced by the combination therapy. Conclusions: This study demonstrates the synergistic efficacy of H3B-6527 and oxaliplatin in promoting apoptosis, enhancing DNA damage, and inhibiting tumor proliferation in gastric cancer models. These findings provide compelling evidence for the potential clinical application of this drug combination as a promising therapeutic strategy for gastric cancer patients, especially those with chemoresistance. Citation Format: Nadeem Bhat, Mohammed Soutto, Ahmed Gomaa, Shoumin Zhu, Selma Maacha, Marwah Al-Mathkour, Mohammed Chwihne, Ahmed El-Rifai, Oliver McDonald, Wael El-Rifai. Synergistic efficacy of FGFR4 inhibitor (H3B-6527) and oxaliplatin combination therapy in gastric cancer models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 1672.