Genomic screening reveals UBA1 as a potent and druggable target in c-MYC-high TNBC models [article]

Sheeba Jacob, Tia H Turner, Jinyang Cai, Konstantinos V Floros, Ann K Yu, Colin M Coon, Rishabh Khatri, Mohammad A Alzubi, Charles T Jakubik, Ynes M Bouck, Madhavi Puchalapalli, Mayuri Shende (+8 others)
2022 bioRxiv   pre-print
Triple negative breast cancer (TNBC) accounts for over 30% of all breast cancer-related deaths, despite accounting for only 10% to 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
more » ... 1). 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.
doi:10.1101/2022.05.17.491908 fatcat:dhxr62twf5ewzgdkzfqy3o4ch4