The overexpression of TS is not the only mechanism of drug resistance in TS-targeted treatment, which also includes an altered expression of some other enzymes related to the folate cycle including dihydrofolate reductase (DHFR), glycinamide ribonucleotide formyl-transferase (GARFT), serine hydroxymethyl transferase (SHMT) and dihydropyrimidine dehydrogenase (DPD), making cancer cells resistant to antimetabolites and fluoropyrimidines (Taddia et al., 2015; D’Arca et al., 2023). The gene discussed is DHFR; the disease is cancer.