Of note, pemetrexed itself, currently used to treat NSCLC patients, inhibits several folate-dependent enzymes such as DHFR, glycinamide ribonucleotide formyl-transferase (GARFT), 5-aminoimidazole-4-carboxamide ribonucleotide formyl-transferase (AICARFT), and thymidylate synthase (TS) which uses 5,10-methylene tetrahydrofolate to convert dUMP into thymidylate, with the release of dihydrofolate in the intracellular folate pool [45]. Here, DHFR is linked to non-small cell lung carcinoma.