Radiosensitization by the Selective Pan-FGFR Inhibitor LY2874455.
Narisa Dewi Maulany DarwisEisuke HorigomeShan LiAkiko AdachiTakahiro OikeAtsushi ShibataYuka HirotaTatsuya OhnoPublished in: Cells (2022)
Ionizing radiation activates cytoprotective pathways in cancer cells. Fibroblast growth factor receptor (FGFR) is a key player in these pathways. Thus, FGFR signaling is a potential target to induce radiosensitization. LY2874455 is an orally administrable selective pan-FGFR inhibitor. However, the radiosensitizing effects of LY2874455 remain unclear. In this study, we addressed this issue by using radioresistant human cancer cell lines H1703 ( FGFR1 mutant), A549 ( FGFR1-4 wild-type), and H1299 ( FGFR1-4 wild-type). At an X-ray dose corresponding to 50%-clonogenic survival as the endpoint, 100 nM LY2874455 increased the sensitivity of H1703, A549, and H1299 cells by 31%, 62%, and 53%, respectively. The combination of X-rays and LY2874455 led to a marked induction of mitotic catastrophe, a hallmark of radiation-induced cell death. Furthermore, combination treatment suppressed the growth of A549 xenografts to a significantly greater extent than either X-rays or the drug alone without noticeable toxicity. This is the first report to show the radiosensitizing effect of a selective pan-FGFR inhibitor. These data suggest the potential efficacy of LY2874455 as a radiosensitizer, warranting clinical validation.
Keyphrases
- wild type
- radiation induced
- cell death
- endothelial cells
- cell cycle arrest
- squamous cell carcinoma
- emergency department
- machine learning
- induced apoptosis
- computed tomography
- cell cycle
- oxidative stress
- cell proliferation
- risk assessment
- signaling pathway
- young adults
- human health
- drug induced
- binding protein
- artificial intelligence