{"doi":"10.1101/2022.08.12.503669","title":"Metabolic adaptations underpin resistance to histone acetyltransferase inhibition","abstract":"Abstract Histone acetyltransferases (HAT) catalyze the acylation of lysine side chains and are implicated in diverse human cancers as both oncogenes and non-oncogene dependencies 1 . Acetyl-CoA-competitive HAT inhibitors have garnered attention as potential cancer therapeutics and the first clinical trial for this class is ongoing ( NCT04606446 ). Despite broad enthusiasm for these targets, notably including CBP/p300 and KAT6A/B 2–5 , the potential mechanisms of therapeutic response and evolved drug resistance remain poorly understood. Using comparative transcriptional genomics, we found that the direct gene regulatory consequences of CBP/p300 HAT inhibition are indistinguishable in models of intrinsically hypersensitive and insensitive acute myeloid leukemia (AML). We therefore modelled acquired drug resistance using a forward genetic selection and identified dysregulation of coenzyme A (CoA) metabolism as a facile driver of resistance to HAT inhibitors. Specifically, drug resistance selected for mutations in PANK3 , a pantothenate kinase that controls the rate limiting step in CoA biosynthesis 6 . These mutations prevent negative feedback inhibition, resulting in drastically elevated concentrations of intracellular acetyl-CoA, which directly outcompetes drug-target engagement. This not only impacts the activity of structurally diverse CBP/p300 HAT inhibitors, but also agents related to an investigational KAT6A/B inhibitor that is currently in Phase-1 clinical trials. We further validated these results using a genome-scale CRISPR/Cas9 loss-of-function genetic modifier screen, which identified additional gene-drug interactions between HAT inhibitors and the CoA biosynthetic pathway. Top hits from the screen included the phosphatase, PANK4 , which negatively regulates CoA production and therefore suppresses sensitivity to HAT inhibition upon knockout 7 , as well as the pantothenate transporter, SLC5A6 8 , which enhances sensitivity. Altogether, this work uncovers CoA plasticity as an unexpected but potentially class-wide liability of anti-cancer HAT inhibitors and will therefore buoy future efforts to optimize the efficacy of this new form of targeted therapy.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2022,"id":304030,"datarank":0.10397207708399181,"base_score":0.6931471805599453,"endowment":0.6931471805599453,"self_citation_contribution":0.10397207708399181,"citation_network_contribution":0.0,"self_endowment_contribution":0.10397207708399181,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":1,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9562,"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":767790,"name":"Chitra Subramanian","orcid":"0000-0003-1101-5307","position":1,"is_corresponding":false},{"id":342815,"name":"Eric M. Bilotta","orcid":"0000-0001-7609-3037","position":2,"is_corresponding":false},{"id":563490,"name":"Leopold Garnar-Wortzel","orcid":"0000-0001-5055-7817","position":3,"is_corresponding":false},{"id":491299,"name":"Anissa R. Ramos","orcid":null,"position":4,"is_corresponding":false},{"id":469466,"name":"Yuxiang Zhang","orcid":"0000-0002-5110-5684","position":5,"is_corresponding":false},{"id":469463,"name":"Joshua N. Asiaban","orcid":"0000-0001-6425-012X","position":6,"is_corresponding":false},{"id":441089,"name":"Christopher J. Ott","orcid":null,"position":7,"is_corresponding":false},{"id":469113,"name":"Charles O. Rock","orcid":"0000-0001-8648-4189","position":8,"is_corresponding":false},{"id":116744,"name":"Michael A. Erb","orcid":"0000-0001-9993-3481","position":9,"is_corresponding":false},{"id":116743,"name":"Timothy Bishop","orcid":"0000-0002-0321-7809","position":0,"is_corresponding":true}],"reference_count":54,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-19T00:32:28.468841Z","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":[]}