The DOI matches its Crossref record; 73 of the 73 references it cites were found in a registry or an index.
Distinct initiating events underpin the immune and metabolic heterogeneity of KRAS-mutant lung adenocarcinoma
Open accessAbstract
The KRAS oncoprotein, a critical driver in 33% of lung adenocarcinoma (LUAD), has remained an elusive clinical target due to its perceived undruggable nature. The identification of dependencies borne through common co-occurring mutations are sought to more effectively target KRAS-mutant lung cancer. Approximately 20% of KRAS-mutant LUAD carry loss-of-function mutations in KEAP1, a negative regulator of the antioxidant response transcription factor NFE2L2/NRF2. We demonstrate that Keap1-deficient KrasG12D lung tumors arise from a bronchiolar cell-of-origin, lacking pro-tumorigenic macrophages observed in tumors originating from alveolar cells.Keap1 loss activates the pentose phosphate pathway, inhibition of which, using 6-AN, abrogated tumor growth. These studies highlight alternative therapeutic approaches to specifically target this unique subset of KRAS-mutant LUAD cancers.
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“Moreover, KRAS-driven lung adenocarcinomas with TP53 mutation induce immune cell production, while tumors with KEAP1 mutations rewire metabolism71.”
From The metabolic landscape of RAS-driven cancers from biology to therapy (2021) · cites this paper as [71]
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“This suggests that rather than considering a one-size-fits-all approach to therapy, individualized precision therapies based on co-occurring mutations could be more effective for patients with KRAS-driven cancers71.”
From The metabolic landscape of RAS-driven cancers from biology to therapy (2021) · cites this paper as [71]
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The pentose phosphate pathway in health and disease
TeSlaa, T. A., Ralser, M., Fan, J., & Rabinowitz, J. D. (2023) · Nature Metabolism · doi:10.1038/s42255-023-00863-2 · Cited by 714
The metabolic landscape of RAS-driven cancers from biology to therapy
Mukhopadhyay, S., Vander Heiden, M. G., & McCormick, F. (2021) · Nature Cancer · doi:10.1038/s43018-021-00184-x · Cited by 315
Metabolic networks in mutant KRAS-driven tumours: tissue specificities and the microenvironment
Kerk, S. A., Papagiannakopoulos, T. Y., Shah, Y. M., & Lyssiotis, C. A. (2021) · Nature reviews. Cancer · doi:10.1038/s41568-021-00375-9 · Cited by 246
Targeting mTOR and Metabolism in Cancer: Lessons and Innovations
Magaway, C., Kim, E., & Jacinto, E. (2019) · Cells · doi:10.3390/cells8121584 · Cited by 231
NRF2: KEAPing Tumors Protected
Pillai, R., Hayashi, M., Zavitsanou, A.-M., & Papagiannakopoulos, T. Y. (2022) · Cancer Discovery · doi:10.1158/2159-8290.cd-21-0922 · Cited by 196
Metadata
- Authors
- Best, S. A., Ding, S., Kersbergen, A., Dong, X., Song, J.-Y., Xie, Y., Reljic, B., Li, K., Vince, J. E., Rathi, V., Wright, G. M., Ritchie, M. E., & Sutherland, K. D.
- Affiliations
- The University of Melbourne (AU)
- Walter and Eliza Hall Institute of Medical Research (AU)
- The Netherlands Cancer Institute (NL)
- Corresponding author
- Sutherland, Kate D.
- ORCID
- Venue
- Nature Communications
- Published
- 2019-09-13
- Volume
- 10
- Issue
- 1
- Pages
- 4190-4190
- ISSN
- 2041-1723 (ISSN-L)
- PMC
- PMC6744438
- OpenAlex
- W2972329402
- Cited by
- 108
- References
- 72
- Citations by year
- 2026: 8 · 2025: 14 · 2024: 14 · 2023: 17 · 2022: 17 · 2021: 22 · 2020: 14 · 2019: 1
- FWCI
- 10.46
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Nature Communications (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Minerva Access (University of Melbourne) (submittedVersion, cc-by)
- RePEc: Research Papers in Economics (submittedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
- Funders
- Department of Health | National Health and Medical Research Council (1138275, 1159002, 1104924)
- Victorian Cancer Agency (18003)
- Peter and Julie Alston WEHI Centenary Fellowship
- Topics
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Lung Cancer Treatments and Mutations
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics, phytochemicals, and oxidative stress
- Keywords
- KRAS-mutant lung adenocarcinoma, pentose phosphate pathway, tumor cell of origin, tumor-associated macrophages, tumor immune heterogeneity, tumor metabolic heterogeneity, KRAS G12D, co-occurring mutations, therapeutic target
- MeSH terms
- Kelch-Like ECH-Associated Protein 1, Adenocarcinoma of Lung, Animals, Carcinoma, Non-Small-Cell Lung, Female, Flow Cytometry, Immunohistochemistry, Lung Neoplasms, Male, Mice, Inbred C57BL, Blotting, Western, Proto-Oncogene Proteins p21(ras), Reactive Oxygen Species, Cell Line, Tumor, NF-E2-Related Factor 2, Mice
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