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NOXA expression drives synthetic lethality to RUNX1 inhibition in pancreatic cancer

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Item Type:Article
Title:NOXA expression drives synthetic lethality to RUNX1 inhibition in pancreatic cancer
Creators Name:Doffo, J. and Bamopoulos, S.A. and Köse, H. and Orben, F. and Zang, C. and Pons, M. and den Dekker, A.T. and Brouwer, R.W.W. and Baluapuri, A. and Habringer, S. and Reichert, M. and Illendula, A. and Krämer, O.H. and Schick, M. and Wolf, E. and van IJcken, W.F.J. and Esposito, I. and Keller, U. and Schneider, G. and Wirth, M.
Abstract:Evasion from drug-induced apoptosis is a crucial mechanism of cancer treatment resistance. The proapoptotic protein NOXA marks an aggressive pancreatic ductal adenocarcinoma (PDAC) subtype. To identify drugs that unleash the death-inducing potential of NOXA, we performed an unbiased drug screening experiment. In NOXA-deficient isogenic cellular models, we identified an inhibitor of the transcription factor heterodimer CBFβ/RUNX1. By genetic gain and loss of function experiments, we validated that the mode of action depends on RUNX1 and NOXA. Of note is that RUNX1 expression is significantly higher in PDACs compared to normal pancreas. We show that pharmacological RUNX1 inhibition significantly blocks tumor growth in vivo and in primary patient-derived PDAC organoids. Through genome-wide analysis, we detected that RUNX1-loss reshapes the epigenetic landscape, which gains H3K27ac enrichment at the NOXA promoter. Our study demonstrates a previously unknown mechanism of NOXA-dependent cell death, which can be triggered pharmaceutically. Therefore, our data show a way to target a therapy-resistant PDAC, an unmet clinical need.
Keywords:NOXA, Apoptosis, PDAC, RUNX1, Pancreatic Cancer
Source:Proceedings of the National Academy of Sciences of the United States of America
ISSN:0027-8424
Publisher:National Academy of Sciences
Volume:119
Number:9
Page Range:e2105691119
Date:1 March 2022
Official Publication:https://doi.org/10.1073/pnas.2105691119
PubMed:View item in PubMed

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