Radiosensitization by the Selective Pan-FGFR Inhibitor LY2874455

Abstract

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.

FGFR families: biological functions and therapeutic interventions in tumors

“…LY2874455 has been found to be useful in gastric and head and neck squamous cell carcinoma, and, notably, as a novel drug, it is resistant to most FGFR mutations resulting in drug resistance, including FGFR4 V550L and FGFR1–561 M, which partially compensates for the lack of futibatinib action, but its specific action needs to be further clarified. Its main side effects include hyperphosphatemia, diarrhea, and stomatitis 364,365 . The inhibitors of FGFR1–3 are pemigatinib, 366 infigratinib, AZD4547, 367 rogaratinib, E7090 and debio 1347.…”

“…Its main side effects include hyperphosphatemia, diarrhea, and stomatitis. 364 , 365 The inhibitors of FGFR1–3 are pemigatinib, 366 infigratinib, AZD4547, 367 rogaratinib, E7090 and debio 1347. Pemigatinib and infigratinib have been approved for cholangiocarcinoma with FGFR fusions or rearrangements.…”