Keap1 loss promotes Kras-driven lung cancer and results in dependence on glutaminolysis
Open accessAbstract
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.
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STK11, TP53 or CDKN2A/CDKN2B co-mutations are frequent in KRAS-mutant tumours, and KRAS-STK11 or KRAS-KEAP1 co-mutation patterns are associated with treatment resistance in preclinical models and poor outcomes in NSCLC patients receiving immune-checkpoint inhibitors with or without chemotherapy.
“co-mutations in the tumour-suppressor genes STK11, TP53 or CDKN2A/CDKN2B are frequently found in KRAS-mutant tumours35. Patients in the KRAS–STK11 co-mutation group can be subdivided into KEAP1-wild-type or KEAP1-mutant subgroups, and KEAP1 can also be co-mutated with KRAS in the absence of STK11 mutations; each of these co-mutation patterns is associated with resistance to treatment in”
From The current state of the art and future trends in RAS-targeted cancer therapies (2022) · cites this paper as [38]
Lung tumor cells with oncogenic KRAS and loss-of-function KEAP1 mutations are more dependent on glutamine and more susceptible to glutaminase inhibition than other cells.
“Cells from advanced lung tumors with oncogenic KRAS and loss-of-function KEAP1 mutations were more dependent on increased amounts of glutamine than other cells, making them more susceptible to glutaminase inhibition62.”
From The metabolic landscape of RAS-driven cancers from biology to therapy (2021) · cites this paper as [62]
NRF2 activation causes glutamine dependence in KRAS-mutant lung and pancreatic cancer cells and preclinical mouse models.
“The activation of NRF2 causes glutamine dependence in KRAS mutant lung and pancreatic cancers cells and preclinical mouse models60,62,63, and BRAF mutants can similarly activate NRF2 to promote reactive oxygen species (ROS) detoxification59.”
From The metabolic landscape of RAS-driven cancers from biology to therapy (2021) · cites this paper as [62]
Co-occurring genomic changes profoundly affect biological behaviors, clinical outcomes, and therapeutic vulnerabilities of KRAS-mutant cancers.
“Compelling evidence showed that co-occurring genomic changes could profoundly affect biological behaviors (29–31), clinical outcomes (32), and therapeutic vulnerabilities of KRAS-mutant cancers (33, 34).”
From New Horizons in KRAS-Mutant Lung Cancer: Dawn After Darkness (2019) · cites this paper as [33]
KEAP1 loss results in increased cellular proliferation in vivo and an altered metabolic profile characterized by increased glucose-derived carbon flux towards the pentose phosphate and serine-glycine biosynthetic pathways with enhanced dependence on glutaminolysis for TCA cycle anaplerosis, a dependence further enhanced by co-occurring LKB1 alterations.
“At the cellular level KEAP1 loss results in increased cellular proliferation in vivo and an altered metabolic profile characterized by increased glucose-derived carbon flux towards the pentose phosphate and serine–glycine biosynthetic pathways93–95 with enhanced dependence on glutaminolysis for tricarboxylic acid (TCA) cycle anaplerosis92, a dependence that is further enhanced by co-occurring LKB1”
From Co-occurring genomic alterations in non-small-cell lung cancer biology and therapy (2019) · cites this paper as [93]
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- Authors
- Romero, R., Sayin, V. I., Davidson, S. M., Bauer, M. R., Singh, S. X., LeBoeuf, S. E., Karakousi, T. R., Ellis, D. C., Bhutkar, A., Sánchez-Rivera, F. J., Subbaraj, L., Martinez, B., Bronson, R. T., Prigge, J. R., Schmidt, E. E., Thomas, C. J., Goparaju, C., Davies, A., Dolgalev, I., Heguy, A., Allaj, V., Poirier, J. T., Moreira, A. L., Rudin, C. M., Pass, H. I., Vander Heiden, M. G., Jacks, T., & Papagiannakopoulos, T.
- Affiliations
- Koch Institute for Integrative Cancer Research At MIT (US)
- NYU Langone Health (US)
- Tufts University (US)
- Montana State University (US)
- National Institutes of Health (US)
- Champions Oncology (United States) (US)
- New York University (US)
- Memorial Sloan Kettering Cancer Center (US)
- Howard Hughes Medical Institute (US)
- Corresponding author
- Jacks, Tyler
- Papagiannakopoulos, Thales
- ORCID
- Romero, Rodrigo
- Sayin, Volkan I
- Davidson, Shawn M
- Bauer, Matthew R
- Singh, Simranjit X
- LeBoeuf, Sarah E
- Karakousi, Triantafyllia R
- Bhutkar, Arjun
- Subbaraj, Lakshmipriya
- Martinez, Britney
- Bronson, Roderick T
- Prigge, Justin R
- Schmidt, Edward E
- Thomas, Craig J
- Goparaju, Chandra
- Dolgalev, Igor
- Heguy, Adriana
- Poirier, John T
- Moreira, Andre L
- Rudin, Charles M
- Pass, Harvey I
- Jacks, Tyler
- Papagiannakopoulos, Thales
- Venue
- Nature Medicine
- Published
- 2017-10-02
- Volume
- 23
- Issue
- 11
- Pages
- 1362-1368
- ISSN
- 1078-8956 (ISSN-L)
- 1546-170X
- PMC
- PMC5677540
- OpenAlex
- W2764232556
- Cited by
- 652
- References
- 71
- Citations by year
- 2026: 58 · 2025: 65 · 2024: 77 · 2023: 74 · 2022: 90 · 2021: 78 · 2020: 91 · 2019: 69 · 2018: 45 · 2017: 4
- FWCI
- 23.80
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Medicine (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- DSpace@MIT (Massachusetts Institute of Technology) (submittedVersion)
- Digital Access to Scholarship at Harvard (DASH) (Harvard University) (submittedVersion, cc-by)
- Funders
- National Science Foundation (1122374, P30-CA14051)
- Howard Hughes Medical Institute
- Hope Funds for Cancer Research
- Wenner-Gren Stiftelserna
- Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology (P30-CA14051)
- European Commission (LTCOFUND2013, 609409)
- Stiftelsen Assar Gabrielssons Fond
- National Institutes of Health (1122374)
- Medical Research Council
- National Heart, Lung, and Blood Institute (T32HL007151)
- National Cancer Institute (R37CA222504, K22CA201088, U01CA111295, CA14051, R01CA227649, P30CA014051, P30CA016087, P30-CA-14051)
- National Institute of General Medical Sciences (T32GM007287)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics, phytochemicals, and oxidative stress
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Lung Cancer Treatments and Mutations
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Keywords
- KRAS mutation, lung adenocarcinoma, Nrf2, glutaminolysis, glutaminase inhibitors, metabolic vulnerability, oxidative stress response, tumor metabolic reprogramming, precision oncology, patient selection for clinical trials
- MeSH terms
- Kelch-Like ECH-Associated Protein 1, Adenocarcinoma of Lung, Adenocarcinoma, Animals, Glutaminase, Glutamine, Humans, Hydrolysis, Lung Neoplasms, Genes, ras, Mice, Clustered Regularly Interspaced Short Palindromic Repeats
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