Shining a light on metabolic vulnerabilities in non-small cell lung cancer
Open accessAbstract
Metabolic reprogramming is a hallmark of cancer which contributes to essential processes required for cell survival, growth, and proliferation. Non-small cell lung cancer (NSCLC) is the most common type of lung cancer and its genomic classification has given rise to the design of therapies targeting tumors harboring specific gene alterations that cause aberrant signaling. Lung tumors are characterized with having high glucose and lactate use, and high heterogeneity in their metabolic pathways. Here we review how NSCLC cells with distinct mutations reprogram their metabolic pathways and highlight the potential metabolic vulnerabilities that might lead to the development of novel therapeutic strategies.
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There are ongoing efforts to utilize metabolic reprogramming in NSCLC as a therapeutic opportunity.
“There are a lot of ongoing efforts to utilize the process of metabolic reprogramming in Non-Small Cell Lung Cancer (NSCLC) as a therapeutic opportunity [21,22,23,24].”
From 20-Hydroxyecdysone Confers Antioxidant and Antineoplastic Properties in Human Non-Small Cell Lung Cancer Cells (2023) · cites this paper as [24]
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BackgroundInfluentialThe AMPK-Related Kinases SIK1 and SIK3 Mediate Key Tumor-Suppressive Effects of LKB1 in NSCLC
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“It has been demonstrated that this activated lipogenesis in KRAS mutant lung adenocarcinoma is via induction of fatty acid synthases through the ERK2-medited pathway [44].”
BackgroundSurvival of Patients with Stage IV Lung Cancer with Diabetes Treated with Metformin
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AIF-regulated oxidative phosphorylation supports lung cancer development
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BackgroundMetabolism and cancer: the future is now
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“This indicates a potential selective pressure existing for the activation of the antioxidant KEAP1/ NRF2 pathway to compensate for oxidative stress induced by LKB1 loss [66].”
BackgroundKRASoncogene in lung cancer: focus on molecularly driven clinical trials
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“Failure to sustain glucose derived ATP production triggers ROS mediated activation of JNK, and subsequently the induction of apoptosis via autophagy-induced EGFR degradation [50].”
BackgroundKeap1 mutation renders lung adenocarcinomas dependent on Slc33a1
Romero, R., Rivera, F. J. S., Westcott, P. M. K., Mercer, K. L., Bhutkar, A. J., Muir, A., González-Robles, T. J., Rodríguez, S. L., Liao, L. Z., Ng, S. R., et al. (2020) · Nature Cancer · doi:10.1038/s43018-020-0071-1 · Cited by 75 · cited 4× · see citing works
“SLC33A1 is an ER-localized transmembrane protein and its loss leads to an induction of the unfolded protein response [90].”
BackgroundInfluentialMetabolic and metastatic characteristics of ALK-rearranged lung adenocarcinoma on FDG PET/CT
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“Interestingly, patients with ALK-rearrangements display higher glucose metabolism and a quicker rate of metastasis when compared to EGFR wild type and mutated tumors [92].”
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“Treatment with phenformin or erlotinib induces mitochondrial damage, impaired ATP homeostasis and an increase in ROS levels in LKB1-deficient cells [67, 76].”
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“Moreover, there is an increase in GLUT1 expression and glucose uptake in TKI resistant NSCLC cells and ablation of GLUT1 re-sensitizes resistant cells to gefitinib [56].”
BackgroundDe novo lipogenesis represents a therapeutic target in mutant Kras non‐small cell lung cancer
Singh, A., Ruiz, C. F., Bhalla, K., Haley, J. D., Li, Q. K., Acquaah-Mensah, G. K., Montal, E. D., Sudini, K. R., Skoulidis, F., Wistuba, I. I., et al. (2018) · The FASEB Journal · doi:10.1096/fj.201800204 · Cited by 55 · see citing works
Exploiting metabolic vulnerabilities of Non small cell lung carcinoma
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“Based on histological and pathological features, this disease is classified as adenocarcinoma (LUAD), squamous cell carcinoma (LUSC) and large cell carcinoma [14].”
BackgroundPIK3CA mutant tumors depend on oxoglutarate dehydrogenase
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BackgroundInhibition of SREBP increases gefitinib sensitivity in non-small cell lung cancer cells
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“Interestingly, sterol regulatory element binding proteins (SREBP) are a family of transcription binding proteins which regulate genes involved in fatty acid synthesis and inhibition of the SREBP driven lipogenic program increases sensitivity to gefitinib in vitro and in vivo [62].”
BackgroundLKB1 promotes metabolic flexibility in response to energy stress
Parker, S. J., Svensson, R. U., Divakaruni, A. S., Lefebvre, A. E. Y. T., Murphy, A. N., Shaw, R. J., & Metallo, C. M. (2016) · Metabolic Engineering · doi:10.1016/j.ymben.2016.12.010 · Cited by 52 · cited 4× · see citing works
“reduction in metabolic plasticity when dealing with energy crisis [70, 73].”
BackgroundInfluentialREDD1 loss reprograms lipid metabolism to drive progression of RAS mutant tumorsPreprint
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“REDD1 loss triggers enhanced uptake of lysophospholipids and lipid storage, coupled to augmented FAO and sustained ATP levels, providing a distinct growth advantage for these tumors [46].”
BackgroundHeightening Energetic Stress Selectively Targets LKB1-Deficient Non–Small Cell Lung Cancers
Momcilovic, M., McMickle, R., Abt, E., Seki, A., Simko, S. A., Magyar, C., Stout, D. B., Fishbein, M. C., Walser, T. C., Dubinett, S. M., et al. (2015) · Cancer Research · doi:10.1158/0008-5472.can-15-0797 · Cited by 46 · cited 3× · see citing works
“reduction in metabolic plasticity when dealing with energy crisis [70, 73].”
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“[91] and a significant decrease in glycolysis is observed in EM4-ALK positive xenografts when treated with ALK inhibitors [93].”
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“function KEAP1 mutations occur in approximately 20–30% of lung adenocarcinoma [82, 83] and KEAP1 inactivation accelerates KRAS induced lung tumorigenesis in vivo [84].”
BackgroundAccelerated cellular senescence phenotype of GAPDH-depleted human lung carcinoma cells
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“Glyceraldehyde 3-phosphate dehydrogenase (GAPDH) is a key enzyme in the glycolytic pathway, and deletion in LKB1-deficent NSCLC cells induces senescence as a result of compromised glycolysis and energy crisis [68].”
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“The activation of the glycolytic regulator, 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase-3 (PFKFB3) is required for glycolysis stimulation following EGFR activation and inhibition of PFKFB3 markedly reduces the EGF-mediated increase in glycolysis [55].”
BackgroundOncogenic KRAS Sensitizes Lung Adenocarcinoma to GSK-J4–Induced Metabolic and Oxidative Stress
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“In parallel, recent advances in biochemical and molecular biological tools, such as advances in mass spectrometry [6], unique in silico modelling [7] and technologies to measure metabolite levels in intact tissue [8], have reignited the metabolic field and offered an unprecedented opportunity to dissect cancer metabol…”
BackgroundIncreased glutamine anabolism sensitizes non-small cell lung cancer to gefitinib treatment
Wang, L., Peng, W., Wu, T., Deng, P., & Zhao, Y. (2018) · Cell Death Discovery · doi:10.1038/s41420-018-0086-x · Cited by 34 · cited 1× · see citing works
“Interestingly, NSCLC cells which are resistant to TKIs display increased utilization of glutamine to generate ATP and GSH, whereas TKI sensitive cells display ATP shortage and ROS accumulation leading to cell death [58].”
BackgroundKinetic modelling of quantitative proteome data predicts metabolic reprogramming of liver cancer
Berndt, N., Egners, A., Mastrobuoni, G., Vvedenskaya, O., Fragoulis, A., Dugourd, A. J. F., Bulik, S., Pietzke, M., Bielow, C., van Gassel, R. J. J., et al. (2019) · British Journal of Cancer · doi:10.1038/s41416-019-0659-3 · Cited by 26 · cited 1× · see citing works
“In parallel, recent advances in biochemical and molecular biological tools, such as advances in mass spectrometry [6], unique in silico modelling [7] and technologies to measure metabolite levels in intact tissue [8], have reignited the metabolic field and offered an unprecedented opportunity to dissect cancer metabol…”
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Loss of Rb1 Enhances Glycolytic Metabolism in Kras-Driven Lung Tumors In Vivo
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Impact of metformin use on survival outcomes in non-small cell lung cancer treated with platinum
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Targeting Metabolic Bottlenecks in Lung Cancer
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“NRF2 induced transcription redirects the flow of bioenergetic mass towards antioxidant production, providing proliferative and survival advantages [85, 86].”
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Targeting glutamine metabolism in PIK3CA mutant colorectal cancers
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The path to venetoclax resistance is paved with mutations, metabolism, and more
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Role and therapeutic targeting of glutamine metabolism in non‑small cell lung cancer (Review)
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“This metabolic reprogramming increases the uptake and utilization of both glucose and glutamine, enhancing aerobic glycolysis and glutamine catabolism to promote cell growth (27,28).”
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Altered expression of ACOX2 in non-small cell lung cancer
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Research Progress in Elucidating the Mechanisms Underlying Resveratrol Action on Lung Cancer
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BackgroundDecoding temporal heterogeneity in NSCLC through machine learning and prognostic model construction
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Additional file 1 of Altered expression of ACOX2 in non-small cell lung cancer
Sui, J. S. Y., Martin, P., Keogh, A., Murchan, P., Ryan, L., Nicholson, S. A., Cuffe, S. D., Broin, P. Ó., Finn, S. P., Fitzmaurice, G. J., et al. (2022) · Figshare · doi:10.6084/m9.figshare.20579709
Yu, J., Pan, K., Wang, N., & Xia, H. (2026) · Research Square · doi:10.21203/rs.3.rs-8592709/v1
Single-cell and spatial transcriptomic technologies for lung cancer tumor microenvironment analysis
Braicu, C., Pîrlog, R., Nutu, A. M., Pruteanu, L.-L., Berindan‐Neagoe, I., & Bender, A. (2026) · Biochimica et Biophysica Acta (BBA) - Reviews on Cancer · doi:10.1016/j.bbcan.2026.189710
- Authors
- Dowling, C. M., Zhang, H., Chonghaile, T. N., & Wong, K.-K.
- Affiliations
- University of Limerick (IE)
- NYU Langone Health (US)
- Royal College of Surgeons in Ireland (IE)
- Corresponding author
- Zhang, Hua
- Wong, Kwok-Kin
- Venue
- Biochimica et Biophysica Acta (BBA) - Reviews on Cancer
- Publisher
- Elsevier BV
- Published
- 2021-01
- Volume
- 1875
- Issue
- 1
- Pages
- 188462
- ISSN
- 0304-419X (ISSN-L)
- PMC
- PMC7836022
- OpenAlex
- W3097767102
- Cited by
- 26
- References
- 136
- Citations by year
- 2026: 3 · 2025: 8 · 2024: 3 · 2023: 3 · 2022: 8 · 2021: 1
- FWCI
- 0.31
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Biochimica et Biophysica Acta (BBA) - Reviews on Cancer (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Figshare (submittedVersion, cc-by-nc-sa)
- Funders
- H2020 MSCA Global Fellowship (799724)
- NIH (CA233084-01, CA219670, CA216188)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Lung Cancer Treatments and Mutations
- Keywords
- non-small cell lung cancer, tumor metabolic reprogramming, metabolic vulnerability, tumor heterogeneity, glucose metabolism, lactate metabolism, genetic mutations
- MeSH terms
- Carcinoma, Non-Small-Cell Lung, Humans, Metabolism, Mutation, Signal Transduction, Cellular Reprogramming
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