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bioRxiv · 10.1101/849927

Inhibition of TXNRD or SOD1 overcomes NRF2-mediated resistance to β-lapachone

Torrente, L.·Prieto, N.·Falzone, A.·Boothman, D. A.·Haura, E. B.·DeNicola, G. M.
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Abstract

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 {beta}-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 {beta}-lapachone treatment remains unknown. To address this question, we assessed the cytotoxicity of {beta}-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 {beta}-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 {beta}-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 {beta}-lapachone, while depletion of catalase or glutathione was ineffective. Interestingly, inhibition of SOD1 selectively sensitized KEAP1 mutant cells to {beta}-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. HighlightsO_LIAberrant activation of NRF2 in non-small cell lung cancer promotes resistance to {beta}-lapachone via the antioxidant defense. C_LIO_LIInhibition of the thioredoxin-dependent system and superoxide dismutase 1 increase sensitivity to {beta}-lapachone treatment. C_LIO_LIMutations in the NRF2/KEAP1 pathway might serve as predictive biomarker for response to {beta}-lapachone in patients. C_LI

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Torrente, L., Prieto, N., Falzone, A., Boothman, D. A., Haura, E. B., DeNicola, G. M.. 2019-11-25. Inhibition of TXNRD or SOD1 overcomes NRF2-mediated resistance to β-lapachone. https://doi.org/10.1101/849927

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