NOXA expression drives synthetic lethality to RUNX1 inhibition in pancreatic cancer

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 CBFb/RUNX1. By genetic gain and loss of function experiments we validated that the mode of action depends on RUNX1 and NOXA. We have performed multiomics analyses as described below. MiaPaCa-2 cells were treated with AI-10-49 and DMSO as vehicle control for 6h. Transcriptome analysis was performed by RNA-seq in n=3 biological replicates. ChIPseq experiments were performed in n=2 biological replicates using the antibodies CTCF, H3K27ac and RUNX1. ATACseq experiments were performed in AI-10-49 and DMSO treated MiaPaCa-2 cells (6h) and in MiaPaCa-2 RUNX1 knockout cells in n=2 biological replicates. Chromosome conformation capture coupled to high-throughput sequencing (4C-Seq) have been performed using the NOXA promoter as viewpoint.