{"doi":"10.1101/2022.05.17.491908","title":"Genomic screening reveals UBA1 as a potent and druggable target in c-MYC-high TNBC models","abstract":"Abstract Triple negative breast cancer (TNBC) accounts for over 30% of all breast cancer-related deaths, despite accounting for only 10%–15% of total breast cancer cases. Targeted therapy development has largely stalled in TNBC, underlined by a lack of traditionally druggable addictions like receptor tyrosine kinases (RTKs). Here, through full genome CRISPR/Cas9 screening of TNBC models, we have uncovered the sensitivity of TNBCs to the depletion of the Ubiquitin-Like Modifier Activating Enzyme 1 (UBA1). Targeting UBA1 with the first in-class UBA1 inhibitor TAK-243 induced unresolvable ER-stress and activating transcription factor 4 (ATF4)-mediated upregulation of pro-apoptotic NOXA, leading to cell death. In five patient derived xenograft models (PDXs) of TNBC, TAK-243 therapy led to tumor inhibition or frank tumor regression. In an intracardiac metastatic model of TNBC, TAK-243 markedly reduced metastatic burden. Importantly, there was an order of magnitude greater sensitivity of TNBC lines to TAK-243 compared to normal tissue-derived cells. Lastly, c-MYC expression correlates with TAK-243 sensitivity and cooperates with TAK-243 to induce a stress response and cell death. We posit UBA1 is an important new target in TNBC expressing high levels of c-MYC. Significance Genomic screening of TNBC cell lines revealed broad sensitivity to depletion of the E1 ubiquitin enzyme, UBA1. Disrupting UBA1 with the first in-class inhibitor TAK-243 in TNBC models induces ER-stress through an ATF4-NOXA axis that is dependent on c-MYC, leading to apoptosis, in vitro and in vivo, primary tumor growth inhibition and metastatic inhibition.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2022,"id":308683,"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":0.9515,"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":825824,"name":"Tia H. Turner","orcid":"0000-0002-6284-4933","position":1,"is_corresponding":false},{"id":512885,"name":"Jinyang Cai","orcid":"0000-0002-7385-8281","position":2,"is_corresponding":false},{"id":519467,"name":"Konstantinos V. Floros","orcid":"0000-0003-4916-2257","position":3,"is_corresponding":false},{"id":943602,"name":"Ann K. Yu","orcid":null,"position":4,"is_corresponding":false},{"id":629143,"name":"Colin M. Coon","orcid":null,"position":5,"is_corresponding":false},{"id":943603,"name":"Rishabh Khatri","orcid":null,"position":6,"is_corresponding":false},{"id":825825,"name":"Mohammad A. Alzubi","orcid":"0000-0002-8788-5440","position":7,"is_corresponding":false},{"id":943027,"name":"Charles T. Jakubik","orcid":"0000-0002-3151-312X","position":8,"is_corresponding":false},{"id":943604,"name":"Ynes M Bouck","orcid":null,"position":9,"is_corresponding":false},{"id":627665,"name":"Madhavi Puchalapalli","orcid":"0000-0002-9827-8697","position":10,"is_corresponding":false},{"id":627663,"name":"Mayuri Shende","orcid":"0000-0002-5095-7295","position":11,"is_corresponding":false},{"id":265858,"name":"Mikhail G. Dozmorov","orcid":"0000-0002-0086-8358","position":12,"is_corresponding":false},{"id":561527,"name":"Sosipatros A. Boikos","orcid":"0000-0002-8608-6962","position":13,"is_corresponding":false},{"id":369681,"name":"Bin Hu","orcid":"0000-0003-2171-2202","position":14,"is_corresponding":false},{"id":292566,"name":"J. Chuck Harrell","orcid":"0000-0003-3541-8418","position":15,"is_corresponding":false},{"id":620641,"name":"Cyril H. Benes","orcid":"0000-0002-8751-9707","position":16,"is_corresponding":false},{"id":344255,"name":"Jennifer E. Koblinski","orcid":"0000-0002-7156-2030","position":17,"is_corresponding":false},{"id":599948,"name":"Carlotta Costa","orcid":"0000-0002-1199-2485","position":18,"is_corresponding":false},{"id":519468,"name":"Anthony C. Faber","orcid":"0000-0002-7246-4272","position":19,"is_corresponding":false},{"id":627661,"name":"Sheeba Jacob","orcid":"0000-0002-6515-0697","position":0,"is_corresponding":true}],"reference_count":51,"raw_metadata":null,"created_at":"2026-07-19T00:33:07.132912Z","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":[]}