A CRISPR screen identifies redox vulnerabilities for KEAP1/NRF2 mutant non-small cell lung cancer

Chang Jiang, Nathan P. Ward, Nicolas Prieto-Farigua, Yun Pyo Kang, Anish Thalakola, Mingxiang Teng, Gina M. DeNicola
2022 · doi:10.1101/2022.03.08.483452
preprint OA: closed CC-BY-NC-4.0
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Abstract

ABSTRACT The redox regulator NRF2 is hyperactivated in a large percentage of non-small cell lung cancer (NSCLC) cases, which is associated with chemotherapy and radiation resistance. To identify redox vulnerabilities for KEAP1/NRF2 mutant NSCLC, we conducted a CRISPR-Cas9-based negative selection screen for antioxidant enzyme genes whose loss sensitized cells to sub-lethal concentrations of the superoxide (O 2 • − )-generating drug β-Lapachone. While our screen identified expected hits in the pentose phosphate pathway, the thioredoxin-dependent antioxidant system, and glutathione reductase, we also identified the mitochondrial superoxide dismutase 2 (SOD2) as one of the top hits. Surprisingly, β-Lapachone did not generate mitochondrial O 2 • − but rather SOD2 loss enhanced the efficacy of β-Lapachone due to loss of iron-sulfur protein function, loss of mitochondrial ATP maintenance and deficient NADPH production. Importantly, inhibition of mitochondrial electron transport activity sensitized to β-Lapachone, demonstrating these effects may be translated to increase ROS sensitivity therapeutically.

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License: CC-BY-NC-4.0