Genomic screening reveals ubiquitin-like modifier activating enzyme 1 as a potent and druggable target in c-MYC-high triple negative breast cancer models. Issue 5 (11th October 2022)

• Record Type: Journal Article
• Authors: Jacob, Sheeba; Turner, Tia H; Cai, Jinyang; Floros, Konstantinos V; Yu, Ann K; Coon, Colin M; Khatri, Rishabh; Alzubi, Mohammad A; Jakubik, Charles T; Bouck, Ynes M; Puchalapalli, Madhavi; Shende, Mayuri; Dozmorov, Mikhail G; Boikos, Sosipatros A; Hu, Bin; Harrell, J Chuck; Benes, Cyril H; Koblinski, Jennifer E; Costa, Carlotta; Faber, Anthony C
• Editors: Levine, Bruce
• Is Part Of: PNAS nexus. Volume 1:Issue 5(2022)
• Publication Date: 2022-10-11
• Subjects: UBA1 -- ER stress -- CRISPR -- targeted therapies -- c-MYC; Science -- Periodicals; 505
• DOI: 10.1093/pnasnexus/pgac232
• Languages: English
• ISSNs: 2752-6542

Abstract

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.