Nf1 loss promotes Kras-driven lung adenocarcinoma and results in Psat1-mediated glutamate dependence
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Abstract Mutations to KRAS are recurrent in lung adenocarcinomas (LUAD) and are daunting to treat due to the difficulties in KRAS oncoprotein inhibition. A possible resolution to this problem may lie with co‐mutations to other genes that also occur in KRAS ‐driven LUAD that may provide alternative therapeutic vulnerabilities. Approximately 3% of KRAS ‐mutant LUADs carry functional mutations in NF1 gene encoding neurofibromin‐1, a negative regulator of focal adhesion kinase 1 (FAK1). We evaluated the impact of Nf1 loss on LUAD development using a CRISPR/Cas9 platform in a murine model of Kras ‐mutant LUAD. We discovered that Nf1 deactivation is associated with Fak1 hyperactivation and phosphoserine aminotransferase 1 (Psat1) upregulation in mice. Nf1 loss also accelerates murine Kras ‐driven LUAD tumorigenesis. Analysis of the transcriptome and metabolome reveals that LUAD cells with mutation to Nf1 are addicted to glutamine metabolism. We also reveal that this metabolic vulnerability can be leveraged as a treatment option by pharmacologically inhibiting glutaminase and/or Psat1. Lastly, the findings advocate that tumor stratification by co‐mutations to KRAS/NF1 highlights the LAUD patient population expected to be susceptible to inhibiting PSAT1.
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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 [34]
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References 44 · Cited by 33
- Authors
- Wang, X., Min, S., Liu, H., Wu, N., Liu, X., Wang, T., Li, W., Shen, Y., Wang, H., Qian, Z., Xu, H., Zhao, C., & Chen, Y.
- Affiliations
- Bengbu Medical College (CN)
- Shanghai Jiao Tong University (CN)
- Corresponding author
- Wang, Xiaojing
- Chen, Yuqing
- ORCID
- Venue
- EMBO Molecular Medicine
- Published
- 2019-04-29
- Volume
- 11
- Issue
- 6
- ISSN
- 1757-4676 (ISSN-L)
- 1757-4684
- PMC
- PMC6554671
- OpenAlex
- W2943484891
- Cited by
- 33
- References
- 44
- Citations by year
- 2026: 5 · 2025: 6 · 2024: 1 · 2023: 3 · 2022: 3 · 2021: 10 · 2020: 3 · 2019: 2
- FWCI
- 3.49
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- EMBO Molecular Medicine (publishedVersion, other-oa)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
- Funders
- NSFC | National Natural Science Foundation of China (81772493)
- Key Program of Natural Science Research of Higher Education of Anhui Province (KJ2017A241)
- Science and Technology Program of Anhui Province (2017070503B037, YDZX20183400002554)
- Topics
- 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
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer Genomics and Diagnostics
- Keywords
- lung adenocarcinoma, KRAS mutation, NF1 loss, neurofibromin 1, PSAT1, glutamine metabolism, glutamine addiction, glutaminase inhibition, co-occurring mutations, tumor stratification, CRISPR/Cas9 mouse model
- MeSH terms
- Adenocarcinoma of Lung, Transaminases, Animals, Cell Line, Humans, Lung Neoplasms, Mutation, Proto-Oncogene Proteins p21(ras), Mice, Knockout, Glutamic Acid, Xenograft Model Antitumor Assays, Neurofibromin 1, Mice, Focal Adhesion Kinase 1
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