Targeted inhibition of EGFR and glutaminase induces metabolic crisis in EGFR mutant lung cancer
Open accessAbstract
Cancer cells exhibit increased use of nutrients, including glucose and glutamine, to support the bioenergetic and biosynthetic demands of proliferation. We tested the small-molecule inhibitor of glutaminase CB-839 in combination with erlotinib on epidermal growth factor receptor (EGFR) mutant non-small cell lung cancer (NSCLC) as a therapeutic strategy to simultaneously impair cancer glucose and glutamine utilization and thereby suppress tumor growth. Here, we show that CB-839 cooperates with erlotinib to drive energetic stress and activate the AMP-activated protein kinase (AMPK) pathway in EGFR (del19) lung tumors. Tumor cells undergo metabolic crisis and cell death, resulting in rapid tumor regression in vivo in mouse NSCLC xenografts. Consistently, positron emission tomography (PET) imaging with 18 F-fluoro-2-deoxyglucose ( 18 F-FDG) and 11 C-glutamine ( 11 C-Gln) of xenografts indicated reduced glucose and glutamine uptake in tumors following treatment with CB-839 + erlotinib. Therefore, PET imaging with 18 F-FDG and 11 C-Gln tracers can be used to non-invasively measure metabolic response to CB-839 and erlotinib combination therapy.
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Inhibiting GLS1 reversed acquired resistance to erlotinib in non-small cell lung cancer in recent preclinical studies.
“recent preclinical studies have shown that inhibiting GLS1 reversed acquired resistance to erlotinib, an EGFR tyrosine kinase inhibitor, in NSCLC [42,43].”
From Combined blockade of EGFR and glutamine metabolism in preclinical models of colorectal cancer (2020) · cites this paper as [43]
The Results section on EGFR-mutant NSCLC xenografts (page unavailable) reports that the GLS inhibitor CB-839 combined with erlotinib delayed tumor regrowth after treatment. That supports a more durable preclinical response, but the paper does not show GLS inhibition reversing resistance already acquired to erlotinib. (LLM, conf=0.89)
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References 36 · Cited by 157
- Authors
- Momcilovic, M., Bailey, S. T., Lee, J. T., Fishbein, M. C., Magyar, C., Braas, D., Graeber, T., Jackson, N. J., Czernin, J., Emberley, E., Gross, M., Janes, J., Mackinnon, A., Pan, A., Rodriguez, M., Works, M., Zhang, W., Parlati, F., Demo, S., Garon, E., Krysan, K., Walser, T. C., Dubinett, S. M., Sadeghi, S., Christofk, H. R., & Shackelford, D. B.
- Affiliations
- University of California, Los Angeles (US)
- Calithera (United States) (US)
- Corresponding author
- Shackelford, David B.
- ORCID
- Venue
- Cell Reports
- Publisher
- Elsevier BV
- Published
- 2017-01
- Volume
- 18
- Issue
- 3
- Pages
- 601-610
- ISSN
- 2211-1247 (ISSN-L)
- PMC
- PMC5260616
- OpenAlex
- W2575507470
- Cited by
- 157
- References
- 36
- Citations by year
- 2026: 8 · 2025: 9 · 2024: 13 · 2023: 13 · 2022: 14 · 2021: 21 · 2020: 31 · 2019: 20 · 2018: 15 · 2017: 12 · 2016: 1
- FWCI
- 7.16
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Cell Reports (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- eScholarship (California Digital Library) (submittedVersion, cc-by-nc-nd)
- Funders
- CTSI and KL2 Translational Science Award (KL2TR000122, UL1TR000124)
- UCLA David Geffen School of Medicine
- Kure It Cancer Research Foundation
- STOP CANCER Foundation
- DOD Lung Cancer Research Program Translational Research Partnership (W81XWH-13-1-0459)
- NIH (HL072752)
- CTSI (UL1TR000124)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Lung Cancer Treatments and Mutations
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Keywords
- EGFR-mutant non-small cell lung cancer, glutaminase inhibition, CB-839, erlotinib, combination therapy, cancer metabolism, glutamine utilization, glucose metabolism, AMPK, metabolic crisis, tumor regression, positron emission tomography, 18F-FDG, cancer cell death
- MeSH terms
- Erlotinib Hydrochloride, Animals, Autophagy, Carbon Radioisotopes, Carcinoma, Non-Small-Cell Lung, Glutaminase, Glutamine, Humans, Lung Neoplasms, Mutation, Thiadiazoles, Transplantation, Heterologous, Mice, SCID, Apoptosis, Radiopharmaceuticals, Fluorodeoxyglucose F18, RNA Interference, Benzeneacetamides, Cell Line, Tumor, Mice, AMP-Activated Protein Kinases, ErbB Receptors
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