Details

Autor(en) / Beteiligte

• 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
• Levine, Bruce

Titel

Genomic screening reveals ubiquitin-like modifier activating enzyme 1 as a potent and druggable target in c-MYC-high triple negative breast cancer models

Ist Teil von

• PNAS nexus, 2022-11, Vol.1 (5), p.pgac232-pgac232

Ort / Verlag

England: Oxford University Press

Erscheinungsjahr

2022

Quelle

Free E-Journal (出版社公開部分のみ）

Beschreibungen/Notizen

• 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.