Disrupting Histidine Catabolism Reduces Methotrexate Sensitivity

Methotrexate is a chemotherapeutic drug widely used to treat patients with cancer. Mechanistically, methotrexate inhibits dihydrofolate reductase, an enzyme that that generates the essential nucleotide synthesis cofactor tetrahydrofolate (THF), to suppress DNA and RNA production and induce cell death. Kanarek and colleagues performed a CRISPR/Cas9-based screen to identify genes that regulate methotrexate sensitivity. This screen revealed that depletion of FTCD, which encodes an enzyme required for catabolism of the amino acid histidine, reduced the sensitivity of hematopoietic cancer cell lines to methotrexate. FTCD catalyzes two steps in histidine degradation: (i) metabolism of THF and the histidine breakdown product formiminoglutamic acid to produce 5-formimino THF, and (ii) metabolism of 5-formimino THF to 5,10-methenyl THF. As FTCD utilizes THF for its nonessential activity, FTCD depletion allowed methotrexate-treated cancer cells to maintain THF pools for nucleotide synthesis, despite methotrexate-mediated suppression of THF production. A similar effect was achieved by targeting histidine ammonia lyase (HAL), the rate-limiting enzyme upstream of FTCD in histidine degradation, providing further evidence that histidine catabolism is a major determinant of methotrexate sensitivity. Moreover, HAL expression was higher in methotrexate-sensitive cells, and, in patients with acute lymphoblastic leukemia treated with methotrexate, high HAL expression was linked to better survival. In vivo, histidine supplementation increased methotrexate sensitivity in leukemia-bearing mice, reducing tumor size without an apparent increase in toxicity. As expected, the combination of histidine supplementation with methotrexate treatment reduced THF levels compared with methotrexate alone, indicative of increased flux through the histidine degradation pathway. In addition to elucidating a mechanism by which the histidine degradation pathway regulates methotrexate sensitivity, these findings suggest that histidine supplementation may enhance the therapeutic efficacy of methotrexate in patients with cancer.

Kanarek N, Keys HR, Cantor JR, Lewis CA, Chan SH, Kunchok T, et al. Histidine catabolism is a major determinant of methotrexate sensitivity. Nature 2018 Jul 11 [Epub ahead of print].

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