Glucose-6-phosphate dehydrogenase maintains redox homeostasis and biosynthesis in LKB1-deficient KRAS-driven lung cancer

Taijin Lan, Sara Arastu, Jarrick Lam, Hyungsin Kim, Wenping Wang, Samuel Wang, Vrushank Bhatt, Eduardo Cararo Lopes, Zhixian Hu, Michael Sun, Xuefei Luo, Jonathan M. Ghergurovich, Xiaoyang Su, Joshua D. Rabinowitz, Eileen White and Jessie Yanxiang Guo ()
Additional contact information
Taijin Lan: Rutgers Cancer Institute
Sara Arastu: Rutgers Cancer Institute
Jarrick Lam: Rutgers Cancer Institute
Hyungsin Kim: Rutgers Cancer Institute
Wenping Wang: Rutgers Cancer Institute
Samuel Wang: Rutgers Cancer Institute
Vrushank Bhatt: Rutgers Cancer Institute
Eduardo Cararo Lopes: Rutgers Cancer Institute
Zhixian Hu: Rutgers Cancer Institute
Michael Sun: Rutgers Cancer Institute
Xuefei Luo: Rutgers Cancer Institute
Jonathan M. Ghergurovich: Princeton University
Xiaoyang Su: Rutgers Cancer Institute
Joshua D. Rabinowitz: Rutgers Cancer Institute
Eileen White: Rutgers Cancer Institute
Jessie Yanxiang Guo: Rutgers Cancer Institute

Nature Communications, 2024, vol. 15, issue 1, 1-18

Abstract: Abstract Cancer cells depend on nicotinamide adenine dinucleotide phosphate (NADPH) to combat oxidative stress and support reductive biosynthesis. One major NADPH production route is the oxidative pentose phosphate pathway (committed step: glucose-6-phosphate dehydrogenase, G6PD). Alternatives exist and can compensate in some tumors. Here, using genetically-engineered lung cancer mouse models, we show that G6PD ablation significantly suppresses KrasG12D/+;Lkb1-/- (KL) but not KrasG12D/+;P53-/- (KP) lung tumorigenesis. In vivo isotope tracing and metabolomics reveal that G6PD ablation significantly impairs NADPH generation, redox balance, and de novo lipogenesis in KL but not KP lung tumors. Mechanistically, in KL tumors, G6PD ablation activates p53, suppressing tumor growth. As tumors progress, G6PD-deficient KL tumors increase an alternative NADPH source from serine-driven one carbon metabolism, rendering associated tumor-derived cell lines sensitive to serine/glycine depletion. Thus, oncogenic driver mutations determine lung cancer dependence on G6PD, whose targeting is a potential therapeutic strategy for tumors harboring KRAS and LKB1 co-mutations.

Date: 2024
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DOI: 10.1038/s41467-024-50157-8

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