Keap1 Loss Drives Kras-Mutant Lung Cancer and Glutaminolysis Dependency

Approximately a third of KRAS-mutant lung adenocarcinoma harbors loss-of-function mutations in KEAP1, which negatively regulates the NF2EL2 (also known as NRF2) antioxidant response pathway. To further elucidate the role of the KEAP1/NRF2 pathway in mutant KRAS-driven lung adenocarcinoma tumorigenesis, Romero and colleagues performed in vivo CRISPR/Cas9 targeting of Keap1 in the autochthonous Kras^G12D/Trp53^−/− (KP) mouse model of lung adenocarcinoma. KP mice harboring CRISPR/Cas9-mediated Keap1 loss exhibited increased nuclear NRF2 accumulation and accelerated tumor growth compared to control KP mice. Analysis of a panel of isogenic KP cell lines generated by CRISPR/Cas9-mediated editing of Nrf2 (KPN) or Keap1 (KPK) revealed that KPK cells, but not KPN cells, were resistant to oxidative stress, and exhibited activation of the NRF2 pathway. Integrated transcriptomic analyses revealed that a core NRF2 signature was upregulated in late-stage lung adenocarcinoma, whereas a mutant KEAP1 transcriptional signature derived from The Cancer Genome Atlas lung adenocarcinoma cohort exhibited enrichment of NRF2 pathway–related genes: Both signatures were associated with worse survival. Similarly, a mutant Keap1 signature derived from Keap1-ablated KP tumors was associated with poor survival. A CRISPR/Cas9 screen targeting NRF2 pathway–related genes in KP and KPK cell lines revealed that the glutamine transporter SLC1A5 was critical for the growth of human and murine lung cancer lines harboring mutant KRAS and mutant KEAP1. Depletion of glutamine reduced the proliferation of KPK, but not KP, cells in vitro, and treatment with small-molecule inhibitors of glutaminase inhibited the growth of KPK cells and human lung cancer cell lines harboring either a loss-of-function KEAP1 mutation or a gain-of-function NRF2 mutation in vitro and in vivo. These results show that KEAP1/NRF2 promotes mutant KRAS-driven lung adenocarcinoma and identify a potential therapeutic strategy for targeting mutant KRAS–driven lung tumors.

Romero R, Sayin VI, Davidson SM, Bauer MR, Singh SX, LeBoeuf SE, et al. Keap1 loss promotes Kras-driven lung cancer and results in dependence on glutaminolysis. Nat Med 2017 Oct 2 [Epub ahead of print].

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