Journal
NATURE MEDICINE
Volume 23, Issue 11, Pages 1362-+Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/nm.4407
Keywords
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Funding
- National Institutes of Health (NIH)
- National Cancer Institute [P30-CA14051]
- American Cancer Society
- Hope Funds for Cancer Research
- NIH [K22CA201088-01, 5T32HL007151-38]
- New York University Department of Pathology Bridge Grant
- National Science Foundation Graduate Research Fellowship [1122374]
- Swedish Medical Research Council
- AG Fond
- Wenner-Gren Foundations
- EMBO long-term fellowship - European Commission [ALTF 1451-2015, LTCOFUND2013, GA-2013-609409]
- National Cancer Institute Early Detection Research Network grant [2U01CA 111295-04]
- Cancer Center Support Grant [P30-CA14051]
- Howard Hughes Medical Institute
- Laura and Isaac Perlmutter Cancer Support Grant
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Treating KRAS-mutant lung adenocarcinoma (LUAD) remains a major challenge in cancer treatment given the difficulties associated with directly inhibiting the KRAS oncoprotein(1). One approach to addressing this challenge is to define mutations that frequently co-occur with those in KRAS, which themselves may lead to therapeutic vulnerabilities in tumors. Approximately 20% of KRAS-mutant LUAD tumors carry loss-of-function mutations in the KEAP1 gene encoding Kelch-like ECH-associated protein 1 (refs. 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 hyperactivates NRF2 and promotes KRAS-driven LUAD in mice. Through a combination of CRISPR-Cas9-based genetic screening and metabolomic analyses, we show that Keap1-or 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 stratification of human patients with lung cancer harboring KRAS/KEAP1-or KRAS/ NRF2-mutant lung tumors as likely to respond to glutaminase inhibition.
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