Nature 559, 632–636 (2018)

Methotrexate is an effective cancer therapy that blocks synthesis of tetrahydrofolate (THF), restricting nucleotide synthesis and proving lethal for cancer cells; however, practitioners often limit its use because of off-target toxicity. In a new study, investigators screened methotrexate-responding cell lines for genes that impacted efficacy and identified the rate-limiting enzyme in histidine catabolism, formimidoyltransferase cyclodeaminase, which consumes THF during catalysis. When considering these and other data, authors speculated that the double whammy of increased histidine degradation and methotrexate would prove useful. Using mice injected with human leukemia cell lines, investigators compared control animals, animals fed supplemental histidine, animals dosed with moderate methotrexate, and animals that received a combination of histidine and methotrexate treatments. Mice receiving the dual intervention showed a significant decrease in tumor size compared to the other groups, paving the way for combination therapies involving diet.