PT  - JOURNAL ARTICLE
AU  - Laura Torrente
AU  - Nicolas Prieto
AU  - Aimee Falzone
AU  - David A. Boothman
AU  - Eric B. Haura
AU  - Gina M. DeNicola
TI  - Inhibition of TXNRD or SOD1 overcomes NRF2-mediated resistance to β-lapachone
AID  - 10.1101/849927
DP  - 2019 Jan 01
TA  - bioRxiv
PG  - 849927
4099  - http://biorxiv.org/content/early/2019/11/25/849927.short
4100  - http://biorxiv.org/content/early/2019/11/25/849927.full
AB  - Alterations in the NRF2/KEAP1 pathway result in the constitutive activation of NRF2, leading to the aberrant induction of antioxidant and detoxification enzymes, including NQO1. The NQO1 bioactivatable agent β-lapachone can target cells with high NQO1 expression but relies in the generation of reactive oxygen species (ROS), which are actively scavenged in cells with NRF2/KEAP1 mutations. However, whether NRF2/KEAP1 mutations influence the response to β-lapachone treatment remains unknown. To address this question, we assessed the cytotoxicity of β-lapachone in a panel of NSCLC cell lines bearing either wild-type or mutant KEAP1. We found that, despite overexpression of NQO1, KEAP1 mutant cells were resistant to β-lapachone due to enhanced detoxification of ROS, which prevented DNA damage and cell death. To evaluate whether specific inhibition of the NRF2-regulated antioxidant enzymes could abrogate resistance to β-lapachone, we systematically inhibited the four major antioxidant cellular systems using genetic and/or pharmacologic approaches. We demonstrated that inhibition of the thioredoxin-dependent system or copper-zinc superoxide dismutase (SOD1) could abrogate NRF2-mediated resistance to β-lapachone, while depletion of catalase or glutathione was ineffective. Interestingly, inhibition of SOD1 selectively sensitized KEAP1 mutant cells to β-lapachone exposure. Our results suggest that NRF2/KEAP1 mutational status might serve as a predictive biomarker for response to NQO1-bioactivatable quinones in patients. Further, our results suggest SOD1 inhibition may have potential utility in combination with other ROS inducers in patients with KEAP1/NRF2 mutations.HighlightsAberrant activation of NRF2 in non-small cell lung cancer promotes resistance to β-lapachone via the antioxidant defense.Inhibition of the thioredoxin-dependent system and superoxide dismutase 1 increase sensitivity to β-lapachone treatment.Mutations in the NRF2/KEAP1 pathway might serve as predictive biomarker for response to β-lapachone in patients.