DNA-PKcs inhibition as a therapeutic approach for differentiated thyroid cancer

DNA-dependent protein kinase catalytic subunit (DNA-PKcs) is a serine-threonine protein kinase that plays critical roles in cellular processes fundamental to cancer. DNA-PKcs may be a potential target for differentiated thyroid cancer (DTC) therapy. A DNA-PKcs inhibitor, M3814, was evaluated for its use in DTC therapy. M3814 caused cytotoxicity in a dose-response fashion in four DTC cell lines (TPC1, K1, FTC-133, and FTC-238). M3814 induced cell cycle arrest at the S phase in DTC cells. M3814 monotherapy was able to repress the growth of the K1 tumor model. M3814 in combination with lenvatinib demonstrated synergism in vitro, and this combination was more effective than any single therapy in an FTC-133 xenograft model. These results reveal that M3814 has significant potential in treating DTC, singly or in drug combination.