| 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 |
| Zdroj: |
PNAS Nexus. 1 |
| ISSN: |
2752-6542 |
| DOI: |
10.1093/pnasnexus/pgac232 |
| Popis: |
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. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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