The chemotherapeutic drug methotrexate inhibits the enzyme dihydrofolate reductase1, which generates tetrahydrofolate, an essential cofactor in nucleotide synthesis2. Depletion of tetrahydrofolate causes cell death by suppressing DNA and RNA production3. Although methotrexate is widely used as an anticancer agent and is the subject of over a thousand ongoing clinical trials4, its high toxicity often leads to the premature termination of its use, which reduces its potential efficacy5. To identify genes that modulate the response of cancer cells to methotrexate, we performed a CRISPR–Cas9-based screen6,7. This screen yielded FTCD, which encodes an enzyme—formimidoyltransferase cyclodeaminase—that is required for the catabolism of the amino acid histidine8, a process that has not previously been linked to methotrexate sensitivity. In cultured cancer cells, depletion of several genes in the histidine degradation pathway markedly decreased sensitivity to methotrexate. Mechanistically, histidine catabolism drains the cellular pool of tetrahydrofolate, which is particularly detrimental to methotrexate-treated cells. Moreover, expression of the rate-limiting enzyme in histidine catabolism is associated with methotrexate sensitivity in cancer cell lines and with survival rate in patients. In vivo dietary supplementation of histidine increased flux through the histidine degradation pathway and enhanced the sensitivity of leukaemia xenografts to methotrexate. The histidine degradation pathway markedly influences the sensitivity of cancer cells to methotrexate and may be exploited to improve methotrexate efficacy through a simple dietary intervention.
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We thank all members of the Sabatini laboratory for their advice and help; W. Chen and L. Shinefeld for helpful comments on the manuscript; M. Pacold for advice; M. Cohen for the R-luciferase expression vector; and M. Lazzara, D. Lauffenburger, M. Zaitseva, A. Al-Katib and R. Jensen for providing cell lines. We thank J. Selhub for advice in the folate field. This work was supported by grants from National Institutes of Health/National Cancer Institute (R01 CA129105) to D.M.S. and the Department of Defense (W81XWH-15-1-0337) to E.F. Fellowship support was provided by the European Molecular Biology Organization (EMBO) (Long-Term Fellowship ALTF 350-2012) and the American Association for Cancer Research (16-40-38-KANA) to N.K., by the American Cancer Society (PF-12-099-01-TBG) and the Koch Institute (Ludwig Postdoctoral Fellowship) to J.R.C., and by the EMBO (Long-Term Fellowship ALTF 1-2014) to M.A.-R. Additional support to N.K. was provided by the Women In Science/Revson Foundation Award (Weizmann Institute) and The Advancement of Women in Science Award (The Hebrew University). D.M.S. is an investigator of the Howard Hughes Medical Institute and an American Cancer Society Research Professor.
Nature thanks C. Frezza and the other anonymous reviewer(s) for their contribution to the peer review of this work.
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