{"doi":"10.1093/pnasnexus/pgac232","title":"Genomic screening reveals ubiquitin-like modifier activating enzyme 1 as a potent and druggable target in c-MYC-high triple negative breast cancer models","abstract":"Triple negative breast cancer (TNBC) accounts for over 30% of all breast cancer (BC)-related deaths, despite accounting for only 10% to 15% of total BC 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 endoplasmic reticulum (ER)-stress and activating transcription factor 4 (ATF4)-mediated upregulation of proapoptotic NOXA, leading to cell death. c-MYC expression correlates with TAK-243 sensitivity and cooperates with TAK-243 to induce a stress response and cell death. Importantly, there was an order of magnitude greater sensitivity of TNBC lines to TAK-243 compared to normal tissue-derived cells. In five patient derived xenograft models (PDXs) of TNBC, TAK-243 therapy led to tumor inhibition or frank tumor regression. Moreover, in an intracardiac metastatic model of TNBC, TAK-243 markedly reduced metastatic burden, indicating UBA1 is a potential new target in TNBC expressing high levels of c-MYC.","journal":"PNAS Nexus","year":2022,"id":274502,"datarank":0.48234974363583194,"base_score":2.3978952727983707,"endowment":2.3978952727983707,"self_citation_contribution":0.3596842909197557,"citation_network_contribution":0.12266545271607628,"self_endowment_contribution":0.3596842909197557,"citer_contribution":0.12266545271607628,"corpus_percentile":null,"corpus_rank":null,"citation_count":10,"citer_count":8,"citers_with_citation_signal":6,"citers_with_endowment":6,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9531,"is_data_producer":true,"deposit_databanks":{"figshare":["10.6084/m9.figshare.19700056.v2"]},"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. 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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":234822,"name":"Bin Hu","orcid":"0000-0002-0278-8466","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. 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