NOXA expression drives synthetic lethality to RUNX1 inhibition in pancreatic cancer.

Proceedings of the National Academy of Sciences of the United States of America 2022 Mar 01

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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. Copyright © 2022 the Author(s). Published by PNAS.

Citation

Josefina Doffo, Stefanos A Bamopoulos, Hazal Köse, Felix Orben, Chuanbing Zang, Miriam Pons, Alexander T den Dekker, Rutger W W Brouwer, Apoorva Baluapuri, Stefan Habringer, Maximillian Reichert, Anuradha Illendula, Oliver H Krämer, Markus Schick, Elmar Wolf, Wilfred F J van IJcken, Irene Esposito, Ulrich Keller, Günter Schneider, Matthias Wirth. NOXA expression drives synthetic lethality to RUNX1 inhibition in pancreatic cancer. Proceedings of the National Academy of Sciences of the United States of America. 2022 Mar 01;119(9)