Romero, RodrigoSayin, Volkan I.Davidson, Shawn M.Bauer, Matthew R.Singh, Simranjit X.LeBoeuf, Sarah E.Karakousi, Triantafyllia R.Ellis, Donald C.Bhutkar, ArjunSanchez-Rivera, Francisco J.Subbaraj, LakshmipriyaMartinez, BritneyBronson, RoderickPrigge, Justin R.Schmidt, Edward E.Thomas, Craig J.Goparaju, ChandraDavies, AngelaDolgalev, IgorHeguy, AdrianaAllaj, ViolaPoirier, John T.Moreira, Andre L.Rudin, Charles M.Pass, Harvey I.Vander Heiden, Matthew G.Jacks, TylerPapagiannakopoulos, Thales2018-05-302017Romero, R., V. I. Sayin, S. M. Davidson, M. R. Bauer, S. X. Singh, S. E. LeBoeuf, T. R. Karakousi, et al. 2017. “Keap1 loss promotes Kras-driven lung cancer and results in a dependence on glutaminolysis.” Nature medicine 23 (11): 1362-1368. doi:10.1038/nm.4407. http://dx.doi.org/10.1038/nm.4407.http://nrs.harvard.edu/urn-3:HUL.InstRepos:37067919Treating KRAS-mutant lung adenocarcinoma (LUAD) remains a major challenge in cancer treatment given the difficulties associated with directly inhibiting the KRAS oncoprotein1. One approach to addressing this challenge is to define frequently co-occurring mutations with KRAS, which themselves may lead to therapeutic vulnerabilities in tumors. Approximately 20% of KRAS-mutant LUAD tumors carry loss-of-function (LOF) mutations in Kelch-like ECH-associated protein 1 (KEAP1)2-4, a negative regulator of nuclear factor erythroid 2-like 2 (NFE2L2; hereafter NRF2), which is the master transcriptional regulator of the endogenous antioxidant response5-10. The high frequency of mutations in KEAP1 suggests an important role for the oxidative stress response in lung tumorigenesis. Using a CRISPR/Cas9-based approach in a mouse model of Kras-driven LUAD we examined the effects of Keap1 loss in lung cancer progression. We show that loss of Keap1 hyper-activates Nrf2 and promotes Kras-driven LUAD. Combining CRISPR/Cas9-based genetic screening and metabolomic analyses, we show that Keap1/Nrf2-mutant cancers are dependent on increased glutaminolysis, and this property can be therapeutically exploited through the pharmacological inhibition of glutaminase. Finally, we provide a rationale for sub-stratification of human lung cancer patients with KRAS-KEAP1 or -NRF2-mutant tumors as likely to respond to glutaminase inhibition.en-USJournal Article2018-05-3010.1038/nm.4407