Abstract
Oxaliplatin, a platinum-based anticancer drug, is commonly used to treat gastrointestinal cancers, including gastric cancer. However, resistance to platinum-based therapies often leads to poor clinical outcomes for gastric cancer patients. Overexpression and activation of FGFR4 signaling have been identified as drivers of tumorigenesis in several types of cancer, including gastric cancer. In this study, we investigated the therapeutic efficacy of combining the FGFR4 inhibitor H3B-6527 with oxaliplatin using in vitro and in vivo gastric cancer models. Using gastric cancer cell lines, cell viability and clonogenic cell survival assays revealed that the combination treatment significantly reduced cancer cell viability and colony formation, compared to either agent alone (p < 0.01). Interestingly, treatment with oxaliplatin alone increased FGFR4 expression in the resistant cancer cell population. Western blot analysis confirmed the heightened DNA damage (γH2AX, cleaved PARP) alongside suppressed pro-survival signals (phospho-STAT3 and BCL2 family). Apoptosis was markedly enhanced, as demonstrated by Caspase-3/7 and TUNEL assays (p < 0.01). In human gastric cancer-derived tumoroids, the combination therapy significantly reduced both the size and number of tumoroids. In patient-derived xenograft (PDX) models, the combined treatment approach outperformed single-agent treatments in reducing tumor growth and improving survival. Immunofluorescence and immunohistochemistry analyses of PDX tumors showed an increase in DNA damage (γH2AX) and apoptosis (cleaved caspase-3) along with a reduction in cell proliferation (KI67). These findings indicate that H3B-6527 enhances gastric cancer sensitivity to oxaliplatin by amplifying DNA damage and disrupting cell survival pathways. This study provides a rationale for clinical trials targeting FGFR4 in gastric cancer.