NR2E3 and pancreatic neoplasm: GEM mediates its activity through multiple DNA-directed pathways including ribonucleotide reductase (RNR) leading to deoxynucleotide depletion, inhibition of DNA polymerase extension, and poisoning of DNA Top1.10,17 Consistent with GEM inducing increased levels of replication stress in PDAC cells, we found that combining it with ATRi (AZD6738) or Wee1i (AZD1775) resulted in increased cytotoxicity relative to single agents in four different pancreatic cancer cell lines (PANC-1, MIA PaCa-2, CFPAC1, HPAF-II) (Figure 5).