{"entity":{"id":"dhfr","kind":"target","name":"Dihydrofolate reductase (DHFR)","aka":[],"tldr":"The enzyme that recycles folate so cells can build DNA. Methotrexate blocks it, which is why folinic acid rescue after high-dose methotrexate matters.","summary":"Dihydrofolate reductase regenerates tetrahydrofolate, the carrier of one-carbon units needed for thymidylate and purine synthesis. Methotrexate is a tight-binding folate analogue that shuts the enzyme down and, as polyglutamates, also inhibits thymidylate synthase; leucovorin bypasses the block in normal tissues, allowing high-dose regimens in acute lymphoblastic leukaemia, osteosarcoma and primary CNS lymphoma. DHFR gene amplification is a classic mechanism of acquired methotrexate resistance, and pemetrexed inhibits DHFR among its folate targets.","asOf":"2026-09-04","wikipedia":"https://en.wikipedia.org/wiki/Dihydrofolate_reductase","links":[{"label":"UniProt P00374: DHFR","url":"https://www.uniprot.org/uniprotkb/P00374/entry"}],"tags":[],"related":[],"cancers":["all-leukemia","osteosarcoma","primary-cns-lymphoma"],"sections":[],"technologies":[],"targets":[],"drugs":["methotrexate","pemetrexed"],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"symbol":"DHFR","role":[],"sources":[],"specificity":"broadly-expressed","distribution":"few-types","specificityNote":"Broadly expressed or essential: HPA lists DHFR among essential proteins and finds the RNA at low tissue specificity; the 4 medicines aimed at it (Methotrexate, Pemetrexed, Aminopterin and more) act on the wild-type protein, so normal tissue is exposed and the therapeutic window comes from the tumour's faster division or its dependence on the protein. HPA DHFR: RNA low tissue specificity; no normal tissue stained high; highest cancer staining prostate cancer (1 of 12 high). Distribution: 3 cancer families in the corpus carry a prevalence row, label threshold or catalogue link for it (Leukaemia, Sarcomas (soft tissue, bone, GIST), Lymphoma); Open Targets associates it with 11 specific cancer types at or above 0.5 (non-small cell lung carcinoma, acute lymphoblastic leukemia, breast cancer, mesothelioma, malignant pleural mesothelioma, hereditary neoplastic syndrome and more). (Rule 7 of scripts/fetch-target-specificity.ts.)","specificitySources":[{"label":"Human Protein Atlas DHFR tissue","url":"https://www.proteinatlas.org/ENSG00000228716-DHFR/tissue","note":"RNA tissue and blood lineage specificity, normal tissue antibody staining (version 25.1, CC BY-SA 3.0)"},{"label":"Open Targets ENSG00000228716 associations","url":"https://platform.opentargets.org/target/ENSG00000228716/associations","note":"cancer associations at or above 0.5 (CC0)"}],"hgnc":"HGNC:2861","ensembl":"ENSG00000228716","uniprot":"P00374","entrez":"1719","firstDescribed":1983,"firstDescribedBasis":"sequence","firstDescribedNote":"Earliest sequence paper UniProt cites for the protein: Masters J.N. et al, Gene, 1983, \"The nucleotide sequence of the cDNA coding for the human dihydrofolic acid reductase\".","firstDescribedSource":"https://pubmed.ncbi.nlm.nih.gov/6687716/","biology":"NADPH-dependent reductase maintaining the tetrahydrofolate pool; amplified in methotrexate-resistant cells.","whereFound":["Acute lymphoblastic leukaemia","Osteosarcoma","Primary CNS lymphoma"],"targetClass":"enzyme","prevalence":[{"cancerId":"metastatic-cancer","pct":"all","measure":"Housekeeping enzyme present in every dividing cell (folate recycling); not a selection marker, which is why these drugs are given by cancer type rather than by test."}]},"route":"/targets/dhfr/","neighbours":{"cancer":[{"id":"all-leukemia","kind":"cancer","name":"Acute lymphoblastic leukaemia","route":"/cancers/all-leukemia/"},{"id":"osteosarcoma","kind":"cancer","name":"Osteosarcoma","route":"/cancers/osteosarcoma/"},{"id":"primary-cns-lymphoma","kind":"cancer","name":"Primary CNS lymphoma","route":"/cancers/primary-cns-lymphoma/"}],"drug":[{"id":"aminopterin","kind":"drug","name":"Aminopterin","route":"/drugs/aminopterin/"},{"id":"leucovorin","kind":"drug","name":"Leucovorin (folinic acid)","route":"/drugs/leucovorin/"},{"id":"methotrexate","kind":"drug","name":"Methotrexate","route":"/drugs/methotrexate/"},{"id":"pemetrexed","kind":"drug","name":"Pemetrexed","route":"/drugs/pemetrexed/"}],"target":[{"id":"gart","kind":"target","name":"GART (trifunctional purine synthesis enzyme)","route":"/targets/gart/"},{"id":"impdh2","kind":"target","name":"IMP dehydrogenase (IMPDH2)","route":"/targets/impdh2/"}]}}