Abstract
BACKGROUND: Anaplastic thyroid cancer (ATC) is one of the most aggressive human malignancies and has a poor prognosis. Ataxia telangiectasia mutated and Rad3 related (ATR) is a key regulator for the DNA damage response and a potential target to treat cancer. METHODS: We assessed the efficacy of BAY 1895344, an ATR inhibitor, in three ATC cell lines. RESULTS: BAY 1895344 caused dose-response cytotoxicity in three ATC cell lines. BAY 1895344 induced S-phase and G2-phase arrest, activated caspase-3 activity and induced apoptosis in ATC cells. BAY 1895344 meaningfully retarded the tumor growth of an ATC xenograft model. BAY 1895344 therapy, combined with dabrafenib and trametinib, had synergism in vitro and revealed robust tumor growth suppression in vivo in two xenograft models of ATC harboring mutant BRAF(V600E). Furthermore, the combination of BAY 1895344 with lenvatinib was more effective than either agent alone in a xenograft model of ATC. CONCLUSIONS: These results reveal that BAY 1895344 has potential in treating ATC.