Our study demonstrated that (a) cells with DNA MMR deficiency are sensitive to FTD to the same extent as cells with DNA MMR proficiency despite DNA MMR-deficient cells being more resistant to 5-FU than DNA MMR-proficient cells, (b) cells that are resistant to 5-FU as a result of DNA MMR deficiency and continuous 5-FU exposure are sensitive to FTD, and (c) and that DNA MMR-deficient cells with truncated MBD4 expression produced by a MBD4 frameshift mutation exhibit enhanced FTD cytotoxicity as a result of G2/M arrest. Here, MBD4 is linked to frontotemporal dementia.