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Nat Med. 2017 Nov;23(11):1362-1368. doi: 10.1038/nm.4407. Epub 2017 Oct 2.

Keap1 loss promotes Kras-driven lung cancer and results in dependence on glutaminolysis.

Author information

1
Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.
2
Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.
3
Department of Pathology, New York University School of Medicine, New York, New York, USA.
4
Tufts University, Boston, Massachusetts, USA.
5
Harvard Medical School, Boston, Massachusetts, USA.
6
Department of Immunology and Infectious Diseases, Montana State University, Bozeman, Montana, USA.
7
National Institutes of Health Chemical Genomics Center, Division of Preclinical Innovation, National Center for Advancing Translational Sciences, US National Institutes of Health, Bethesda, Maryland, USA.
8
Department of Cardiothoracic Surgery, New York University Langone Medical Center, New York, New York, USA.
9
Champions Oncology, Hackensack, New Jersey, USA.
10
Genome Technology Center, New York University School of Medicine, New York, New York, USA.
11
Molecular Pharmacology Program, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
12
Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
13
Howard Hughes Medical Institute, Chevy Chase, Maryland, USA.
14
Perlmutter Cancer Center, New York University School of Medicine, New York, New York, USA.

Abstract

Treating KRAS-mutant lung adenocarcinoma (LUAD) remains a major challenge in cancer treatment given the difficulties associated with directly inhibiting the KRAS oncoprotein. 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, 3, 4), a negative regulator of nuclear factor erythroid 2-like 2 (NFE2L2; hereafter NRF2), which is the master transcriptional regulator of the endogenous antioxidant response. 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.

PMID:
28967920
PMCID:
PMC5677540
DOI:
10.1038/nm.4407
[Indexed for MEDLINE]
Free PMC Article

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