{"doi":"10.1101/2022.01.31.478570","title":"Histone deacetylase inhibitor induces acetyl-CoA depletion leading to lethal metabolic stress in RAS-pathway activated cells","abstract":"Abstract RAS-mutant cancers are among the most refractory to treatment. Apart from new G12C genotype targeted therapies, strategies to kill RAS-mutant cells by directly targeting RAS or its downstream effectors have been mostly unsuccessful, mainly due to pathway redundancy and heterogeneities in RAS-induced phenotypes. Here we identified a RAS-phenotype that can be targeted by the histone deacetylase inhibitor (HDACi) romidepsin. We showed that the hyperacetylation induced by romidepsin depleted acetyl-CoA, the cell donor substrate for acetylation, and led to metabolic stress and death in KRAS-activated cells. Elastic net analysis on transcriptomics from a 608-cell panel confirmed that HDACi sensitivity was linked to a difference in profiles in two pathways involved in acetyl-CoA metabolism. The analysis of a clinical dataset confirmed that perturbation of the two acetyl-CoA pathways were correlated with HDACi sensitivity in patients treated with belinostat. Our analysis suggests the potential utility of a RAS-associated acetyl-CoA phenotype to sharpen treatment choices for RAS-activated tumors.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2022,"id":299801,"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":3,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9517,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2022-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":364399,"name":"Pierre-Christian Violet","orcid":"0000-0001-9550-3660","position":1,"is_corresponding":false},{"id":696269,"name":"Maryam Safari","orcid":"0000-0002-4972-6780","position":2,"is_corresponding":false},{"id":378048,"name":"Carole Sourbier","orcid":"0000-0002-4853-7662","position":3,"is_corresponding":false},{"id":51073,"name":"W. Marston Linehan","orcid":"0000-0001-7983-3109","position":4,"is_corresponding":false},{"id":378982,"name":"Robert W. Robey","orcid":"0000-0002-0857-3650","position":5,"is_corresponding":false},{"id":364402,"name":"Mark Levine","orcid":"0000-0001-6297-4650","position":6,"is_corresponding":false},{"id":401702,"name":"Dan L. Sackett","orcid":"0000-0002-3492-1866","position":7,"is_corresponding":false},{"id":3641,"name":"Susan E. Bates","orcid":"0000-0001-6708-0330","position":8,"is_corresponding":false},{"id":696270,"name":"Agnès Basseville","orcid":"0000-0002-9349-1819","position":0,"is_corresponding":true}],"reference_count":35,"raw_metadata":null,"created_at":"2026-07-19T00:31:49.412501Z","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":[]}