NOXA expression drives synthetic lethality to RUNX1 inhibition in pancreatic cancer.
Josefina DoffoStefanos A BamopoulosHazal KöseFelix OrbenChuanbing ZangMiriam PonsAlexander T den DekkerRutger W W BrouwerApoorva BaluapuriStefan HabringerMaximillian ReichertAnuradha IllendulaOliver H KrämerMarkus SchickElmar WolfWilfred F J Van IJckenIrene EspositoUlrich Bernd KellerGünter SchneiderMatthias WirthPublished in: Proceedings of the National Academy of Sciences of the United States of America (2022)
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.
Keyphrases
- transcription factor
- induced apoptosis
- cell death
- poor prognosis
- dna binding
- endoplasmic reticulum stress
- gene expression
- oxidative stress
- signaling pathway
- emergency department
- electronic health record
- genome wide identification
- single cell
- big data
- machine learning
- drug induced
- long non coding rna
- deep learning
- risk assessment