Abstract P1-19-28: Genomic screening reveals UBA1 as a potent and druggable target in diverse models of triple negative breast cancer

摘要: Triple negative breast cancer (TNBC) confers the poorest prognosis of major subtypes cancers, and often inflicts young, African-American Hispanic women. Steadily improving survival in other subsets cancers are attributed to implementation effective targeted therapies, which non-chemotherapy drugs that target a specific gene cancer. For instance, hormone positive BCs treated effectively with anti-hormone therapy, HER2 amplified anti-HER2 therapy. The CRISPR/CRISPR-associated protein-9 nuclease (Cas9) system, enables editing occur throughout genome, allows for broad unbiased discovery new drug targets. We took advantage this system ask whether it may identify druggable targets treat TNBC performed whole genome CRISPR/cas9 screening two cell lines, BT549 MDA-MB-468. To account heterogeneity found TNBC, we further expanded screen into seven by focusing on select number hits from initial screen. This helped us novel ubiquitin activating enzyme 1 (UBA1). recently reported small molecule inhibitor UBA1, TAK-243, is already clinical trial evaluation hematological cancers. Characterization TAK-243 culture models ex-vivo patient-derived xenografts (PDXs) demonstrated nanomolar IC50 toxicity, was significantly lower than tissue-derived normal cells. Mechanistically, therapy induced ER stress unfolded protein response both vitro vivo, leading upregulation activation transcription factor 4 (ATF4) ATF6. Blocking ATF4 led loss NOXA efficacy. tumor regressions PDX TNBC. Overall, these data demonstrate UBA1 Citation Format: Sheeba Jacob, Tia H. Turner, Ann K. Yu, Colin M. Coon, Mohammad A. Alzubi, Charles T. Jakubik, Ynes Bouck, Mikhail G. Dozmorov, Sosipatros Boikos, Jennifer Koblinski, Joshua C. Harrell, Cyril Benes, Carlotta Costa, Anthony Faber. Genomic reveals as potent diverse triple [abstract]. In: Proceedings 2019 San Antonio Breast Cancer Symposium; Dec 10-14; Antonio, TX. Philadelphia (PA): AACR; Res 2020;80(4 Suppl):Abstract nr P1-19-28.