{"doi":"10.1101/2021.11.30.470644","title":"A druggable addiction to <i>de novo</i> pyrimidine biosynthesis in diffuse midline glioma","abstract":"SUMMARY Diffuse midline glioma (DMG) is a uniformly fatal pediatric cancer driven by oncohistones that do not readily lend themselves to drug development. To identify druggable targets for DMG, we conducted a genome-wide CRISPR screen that reveals a DMG selective dependency on the de novo pathway for pyrimidine biosynthesis. This metabolic vulnerability reflects an elevated rate of uridine/uracil degradation that depletes DMG cells of substrates for the alternate salvage pathway for pyrimidine biosynthesis. A clinical stage inhibitor of DHODH (rate limiting enzyme in the de novo pathway) diminishes UMP pools, generates DNA damage, and induces apoptosis through suppression of replication forks--an “on target” effect, as shown by uridine rescue. MALDI mass spectroscopy imaging demonstrates that this DHODH inhibitor (BAY2402234) accumulates in brain at therapeutically relevant concentrations, suppresses de novo pyrimidine biosynthesis in vivo , and prolongs survival of mice bearing intracranial DMG xenografts, highlighting BAY2402234 as a promising therapy against DMGs.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2021,"id":227849,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.953,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2021-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":832677,"name":"Jakub Kaplan","orcid":null,"position":1,"is_corresponding":false},{"id":1804,"name":"Huy Nguyen","orcid":"0000-0002-4424-1047","position":2,"is_corresponding":false},{"id":711845,"name":"Sylwia A. Stopka","orcid":"0000-0003-3761-6899","position":3,"is_corresponding":false},{"id":620762,"name":"Milan R. Savani","orcid":"0000-0003-1776-451X","position":4,"is_corresponding":false},{"id":521205,"name":"Michael S. Regan","orcid":"0000-0001-5252-2829","position":5,"is_corresponding":false},{"id":68700,"name":"Quang‐Dé Nguyen","orcid":null,"position":6,"is_corresponding":false},{"id":683195,"name":"Kristen L. Jones","orcid":"0000-0002-8688-6679","position":7,"is_corresponding":false},{"id":292829,"name":"Lisa A. Moreau","orcid":"0000-0003-2985-0415","position":8,"is_corresponding":false},{"id":832157,"name":"Jingyu Peng","orcid":"0000-0002-8304-9517","position":9,"is_corresponding":false},{"id":832158,"name":"Marina DiPiazza","orcid":"0000-0001-7461-8709","position":10,"is_corresponding":false},{"id":832159,"name":"Andrew J. Perciaccante","orcid":"0000-0002-8698-9651","position":11,"is_corresponding":false},{"id":305651,"name":"Xiaoting Zhu","orcid":"0000-0001-9609-2744","position":12,"is_corresponding":false},{"id":832678,"name":"Bradley R. Hunsel","orcid":null,"position":13,"is_corresponding":false},{"id":257989,"name":"Kevin X. Liu","orcid":"0000-0003-2071-5137","position":14,"is_corresponding":false},{"id":832160,"name":"Rachid Drissi","orcid":"0000-0003-0564-0181","position":15,"is_corresponding":false},{"id":1408,"name":"Mariella G. Filbin","orcid":"0000-0002-2613-8126","position":16,"is_corresponding":false},{"id":278608,"name":"Samuel K. McBrayer","orcid":"0000-0001-9361-675X","position":17,"is_corresponding":false},{"id":521207,"name":"Nathalie Y.R. Agar","orcid":"0000-0003-3149-3146","position":18,"is_corresponding":false},{"id":241556,"name":"Dipanjan Chowdhury","orcid":"0000-0001-5645-3752","position":19,"is_corresponding":false},{"id":1407,"name":"Daphne A. Haas‐Kogan","orcid":"0000-0002-2378-4800","position":20,"is_corresponding":false},{"id":90581,"name":"Sharmistha Pal","orcid":"0000-0001-5391-5149","position":0,"is_corresponding":true}],"reference_count":59,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-18T23:54:46.312854Z","pmid":null,"pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}