Expression of pro-apoptotic NOXA/PMAIP1 drives synthetic lethality upon RUNX1 inhibition in pancreatic cancer
Dr. Matthias Wirth
Charité Universitat Berlin
Cancer treatment resistance is caused primarily by evasion from drug-induced apoptosis. NOXA, a pro-apoptotic member of the BCL2 family, is interestingly associated with aggressive pancreatic ductal adenocarcinoma (PDAC). To identify drugs that activate the death-inducing properties of NOXA, we performed an unbiased drug screening experiment. We identified a substance that inhibits the CBFb/RUNX1 transcription factor heterodimer and validated the mode of action through genetic gain- and loss of function experiments. Remarkably, the expression of RUNX1 in PDAC is significantly higher than in normal pancreas.
Through genome wide analysis, we found that H3K27ac enrichment at the NOXA promoter is induced by loss of RUNX1, which reduces tumor growth in vivo and in primary patient-derived PDAC organoids. This study reveals a previously unknown mechanism of NOXA-dependent cell death that can be triggered pharmaceutically, offering a novel way to target PDAC, a therapy-resistant cancer.
