| Autor: |
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, Mikhail G. Dozmorov, Sosipatros A. Boikos, Bin Hu, J. Chuck Harrell, Cyril H. Benes, Jennifer E. Koblinski, Carlotta Costa, Anthony C. Faber |
| Rok vydání: |
2022 |
| DOI: |
10.1101/2022.05.17.491908 |
| Popis: |
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.SignificanceGenomic 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. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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