NOXA expression drives synthetic lethality to RUNX1 inhibition in pancreatic cancer

Proc Natl Acad Sci U S A. 2022 Mar 1;119(9):e2105691119. doi: 10.1073/pnas.2105691119.

Abstract

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.

Keywords: NOXA; PDAC; RUNX1; apoptosis; pancreatic cancer.

MeSH terms

  • Apoptosis / genetics*
  • Carcinoma, Pancreatic Ductal / genetics*
  • Carcinoma, Pancreatic Ductal / pathology
  • Core Binding Factor Alpha 2 Subunit / antagonists & inhibitors
  • Core Binding Factor Alpha 2 Subunit / genetics*
  • Gene Expression*
  • Humans
  • Pancreatic Neoplasms / genetics*
  • Pancreatic Neoplasms / pathology
  • Promoter Regions, Genetic
  • Proto-Oncogene Proteins c-bcl-2 / genetics*
  • Synthetic Lethal Mutations*
  • Up-Regulation

Substances

  • Core Binding Factor Alpha 2 Subunit
  • PMAIP1 protein, human
  • Proto-Oncogene Proteins c-bcl-2