Paper

NOXA expression drives synthetic lethality to RUNX1 inhibition in pancreatic cancer

Pons, Miriam, Brouwer, Rutger Ww, Schick, Markus, Wolf, Elmar, Schneider, Gunter, Esposito, Irene, Doffo, Josefina, Kramer, Oliver H, Illendula, Anuradha, Habringer, Stefan, Reichert, Maximillian, Den Dekker, Alexander T, Keller, Ulrich, Kose, Hazal, Wirth, Matthias, Bamopoulos, Stefanos A, Baluapuri, Apoorva, Orben, Felix, Wilfred Fj Van Ijcken

2021

Overview

Evasion from drug-induced apoptosis is a crucial mechanism of cancer treatment resistance. The pro-apoptotic 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, 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 novel way to target a therapy resistant PDAC, an unmet clinical need. Competing Interest Statement The authors have declared no competing interest.

• Publisher: Cold Spring Harbor Laboratory Press,Cold Spring Harbor Laboratory
• Subject: Adenocarcinoma / Apoptosis / Cancer Biology / Cell death / Drug screening / Epigenetics / Genomes / Lethality / Organoids / Pancreatic cancer / Runx1 protein / Tumors