NRF2 Promotes Tumor Maintenance by Modulating mRNA Translation in Pancreatic Cancer

Pancreatic cancer is a deadly malignancy that lacks effective therapeutics. We previously reported that oncogenic Kras induced the redox master regulator Nfe2l2/Nrf2 to stimulate pancreatic and lung cancer initiation. Here, we show that NRF2 is necessary to maintain pancreatic cancer proliferation by regulating mRNA translation. Specifically, loss of NRF2 led to defects in autocrine epidermal growth factor receptor (EGFR) signaling and oxidation of specific translational regulatory proteins, resulting in impaired cap-dependent and cap-independent mRNA translation in pancreatic cancer cells. Combined targeting of the EGFR effector AKT and the glutathione antioxidant pathway mimicked Nrf2 ablation to potently inhibit pancreatic cancer ex vivo and in vivo, representing a promising synthetic lethal strategy for treating the disease. [Display omitted] •Nrf2 supports pancreatic tumor maintenance•Nrf2 inhibits oxidation of specific translational regulatory factors•Nrf2 promotes EGFR signaling to fuel cap-dependent mRNA translation•Combined targeting of AKT and glutathione synthesis inhibits pancreatic cancer Pancreatic tumors are sustained through NRF2 which protects regulators of translation from oxidation and potentiates EGFR signaling, supporting a synergistic therapeutic effect of pro-oxidants and small molecules targeting the EGFR effector AKT.