Preclinical evidence that fibroblast growth factor receptor pathway inhibition by BGJ398 enhances small cell lung cancer response to chemotherapy.

Abstract

Small cell lung cancer (SCLC) is a highly aggressive form of lung cancer with limited therapeutic options and poor prognosis. In this study, we explored the therapeutic potential of BGJ398, a selective fibroblast growth factor receptor (FGFR) inhibitor, alone and in combination with standard chemotherapy (cisplatin and paclitaxel) in SCLC. High-throughput screening of kinase inhibitors was performed on three SCLC cell lines (NCI-H446, NCI-H69, and NCI-H182), identifying BGJ398 as one of the most potent and selective inhibitors. BGJ398 demonstrated significant synergy with cisplatin and paclitaxel in vitro, as indicated by combination index values below 1. In vivo, combination treatments significantly inhibited tumor growth and extended survival in SCLC xenograft models compared to monotherapies. Notably, the combination of BGJ398 with cisplatin exhibited the most pronounced tumor suppression and survival benefits. Immunohistochemistry analysis confirmed that BGJ398 effectively inhibited FGFR signaling pathways, reducing levels of phosphorylated FGFR, protein kinase B, signal transducer and activator of transcription 3, and extracellular signal-regulated kinase. These findings suggest that BGJ398, particularly in combination with chemotherapy, holds significant promise as a treatment strategy for SCLC, providing enhanced anti-tumor efficacy and improved survival outcomes.