Targeting MYC-enhanced glycolysis for the treatment of small cell lung cancer
Open accessAbstract
INTRODUCTION: The transcription factor MYC is overexpressed in 30% of small cell lung cancer (SCLC) tumors and is known to modulate the balance between two major pathways of metabolism: glycolysis and mitochondrial respiration. This duality of MYC underscores the importance of further investigation into its role in SCLC metabolism and could lead to insights into metabolic targeting approaches. METHODS: We investigated differences in metabolic pathways in transcriptional and metabolomics datasets based on cMYC expression in patient and cell line samples. Metabolic pathway utilization was evaluated by flow cytometry and Seahorse extracellular flux methodology. Glycolysis inhibition was evaluated in vitro and in vivo using PFK158, a small molecular inhibitor of PFKFB3. RESULTS: MYC-overexpressing SCLC patient samples and cell lines exhibited increased glycolysis gene expression directly mediated by MYC. Further, MYC-overexpressing cell lines displayed enhanced glycolysis consistent with the Warburg effect, while cell lines with low MYC expression appeared more reliant on oxidative metabolism. Inhibition of glycolysis with PFK158 preferentially attenuated glucose uptake, ATP production, and lactate in MYC-overexpressing cell lines. Treatment with PFK158 in xenografts delayed tumor growth and decreased glycolysis gene expression. CONCLUSIONS: Our study highlights an in-depth characterization of SCLC metabolic programming and presents glycolysis as a targetable mechanism downstream of MYC that could offer therapeutic benefit in a subset of SCLC patients.
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Transcription factors c-Myc and ATF4 are two master-regulators of glycolysis, respiration, and one-carbon metabolism.
“Transcription factors c-Myc and ATF4 are two master-regulators of glycolysis, respiration, and one-carbon metabolism [44,45,46,49].”
From 20-Hydroxyecdysone Confers Antioxidant and Antineoplastic Properties in Human Non-Small Cell Lung Cancer Cells (2023) · cites this paper as [45]
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Cites
(1968) · American Association of Industrial Nurses Journal · doi:10.1177/216507996801601208 · Cited by 8,811 · see citing works
First-line atezolizumab plus chemotherapy in extensive-stage small-cell lung cancer
Horn, L., Mansfield, A. S., Szczęsna, A., Havel, L., Krzakowski, M., Hochmair, M. J., Huemer, F., Losonczy, G., Johnson, M. L., Nishio, M., et al. (2018) · New England Journal of Medicine · doi:10.1056/nejmoa1809064 · Cited by 3,586 · see citing works
Reactive oxygen species in cancer
Liou, G., & Störz, P. (2010) · Free Radical Research · doi:10.3109/10715761003667554 · Cited by 3,394 · see citing works
Dang, C. V. (2012) · Cell · doi:10.1016/j.cell.2012.03.003 · Cited by 3,390 · see citing works
Metabolic Competition in the Tumor Microenvironment Is a Driver of Cancer Progression
Chang, C.-H., Qiu, J., O’Sullivan, D., Buck, M. D., Noguchi, T., Curtis, J. D., Chen, Q., Gindin, M., Gubin, M. M., van der Windt, G. J. W., et al. (2015) · Cell · doi:10.1016/j.cell.2015.08.016 · Cited by 3,331 · see citing works
Comprehensive genomic profiles of small cell lung cancer
George, J., Lim, J. S., Jang, S. J., Cun, Y., Ozretić, L., Kong, G., Leenders, F., Lu, X. L., Fernandez‐Cuesta, L., Bosco, G., et al. (2015) · Nature · doi:10.1038/nature14664 · Cited by 2,325 · see citing works
ROS in cancer therapy: the bright side of the moon
Perillo, B., Di Donato, M., Pezone, A., Di Zazzo, E., Giovannelli, P., Galasso, G., Castoria, G., & Migliaccio, A. (2020) · Experimental & Molecular Medicine · doi:10.1038/s12276-020-0384-2 · Cited by 2,176 · see citing works
Inhibitory effect of tumor cell-derived lactic acid on human T cells
Fischer, K., Hoffmann, P., Voelkl, S., Meidenbauer, N., Ammer, J., Edinger, M., Gottfried, E., Schwarz, S., Rothe, G., Hoves, S., et al. (2007) · Blood · doi:10.1182/blood-2006-07-035972 · Cited by 1,946 · see citing works
Non-small cell lung cancer: current treatment and future advances
Zappa, C., & Mousa, S. A. (2016) · Translational Lung Cancer Research · doi:10.21037/tlcr.2016.06.07 · Cited by 1,944 · see citing works
Glutamine addiction: a new therapeutic target in cancer
Wise, D. R., & Thompson, C. B. (2010) · Trends in Biochemical Sciences · doi:10.1016/j.tibs.2010.05.003 · Cited by 1,770 · see citing works
Phosphoenolpyruvate Is a Metabolic Checkpoint of Anti-tumor T Cell Responses
Ho, P.-C., Bihuniak, J. D., Macintyre, A. N., Staron, M., Liu, X., Amezquita, R., Tsui, Y.-C., Cui, G., Micevic, G., Perales, J. C., et al. (2015) · Cell · doi:10.1016/j.cell.2015.08.012 · Cited by 1,462 · see citing works
Integrative genome analyses identify key somatic driver mutations of small-cell lung cancer
Peifer, M., Fernandez‐Cuesta, L., Sos, M. L., George, J., Seidel, D., Kasper, L. H., Plenker, D., Leenders, F., Sun, R., Zander, T., et al. (2012) · Nature Genetics · doi:10.1038/ng.2396 · Cited by 1,390 · see citing works
Lactate Metabolism in Human Lung Tumors
Faubert, B., Li, K. Y., Cai, L., Hensley, C. T., Kim, J., Zacharias, L. G., Yang, C., Do, Q. N., Doucette, S., Burguete, D., et al. (2017) · Cell · doi:10.1016/j.cell.2017.09.019 · Cited by 1,343 · see citing works
Molecular subtypes of small cell lung cancer: a synthesis of human and mouse model data
Rudin, C. M., Poirier, J. T., Byers, L. A., Dive, C., Dowlati, A., George, J., Heymach, J. V., Johnson, J. E. B., Lehman, J. M., MacPherson, D. P., et al. (2019) · Nature reviews. Cancer · doi:10.1038/s41568-019-0133-9 · Cited by 1,251 · see citing works
Self-citationAntonia, S. J., López-Martin, J. A., Bendell, J., Ott, P. A., Taylor, M., Eder, J. P., Jäger, D., Pietanza, M. C., Le, D. T., de Braud, F., et al. (2016) · The Lancet Oncology · doi:10.1016/s1470-2045(16)30098-5 · Cited by 1,244 · see citing works
Metabolic heterogeneity in human lung tumors
Hensley, C. T., Faubert, B., Yuan, Q., Lev-Cohain, N., Jin, E., Kim, J., Jiang, L., Ko, B., Skelton, R., Loudat, L., et al. (2016) · Cell · doi:10.1016/j.cell.2015.12.034 · Cited by 1,138 · see citing works
Carnitine transport and fatty acid oxidation
Longo, N., Frigeni, M., & Pasquali, M. (2016) · Biochimica et Biophysica Acta (BBA) - Molecular Cell Research · doi:10.1016/j.bbamcr.2016.01.023 · Cited by 1,006 · see citing works
The Metabolism of Carcinoma Cells
Warburg, O. H. (1925) · The Journal of Cancer Research · doi:10.1158/jcr.1925.148 · Cited by 1,005 · see citing works
Gay, C. M., Stewart, C. A., Park, E. M., Diao, L., Groves, S. M., Heeke, S., Nabet, B. Y., Fujimoto, J., Solis, L. M., Lü, W., et al. (2021) · Cancer Cell · doi:10.1016/j.ccell.2020.12.014 · Cited by 977 · see citing works
Self-citationMiller, D. M., Thomas, S. D., Islam, A., Muench, D. E., & Sedoris, K. C. (2012) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-12-0977 · Cited by 844 · see citing works
MYC Activation Is a Hallmark of Cancer Initiation and MaintenancePreprint
Gabay, M., Li, Y., & Felsher, D. W. (2014) · Cold Spring Harbor Perspectives in Medicine · doi:10.1101/cshperspect.a014241 · Cited by 808 · see citing works
Targeting oncogenic Myc as a strategy for cancer treatment
Chen, H., Liu, H., & Qing, G. (2018) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-018-0008-7 · Cited by 806 · see citing works
Seyfried, T. N., & Shelton, L. M. (2010) · Nutrition & Metabolism · doi:10.1186/1743-7075-7-7 · Cited by 656 · see citing works
Meuwissen, R., Linn, S. C., Linnoila, R. I., Zevenhoven, J., Mooi, W. J., & Berns, A. (2003) · Cancer Cell · doi:10.1016/s1535-6108(03)00220-4 · Cited by 643 · see citing works
Mollaoglu, G., Guthrie, M. R., Böhm, S., Brägelmann, J., Can, İ., Ballieu, P. M., Marx, A., George, J., Heinen, C., Chalishazar, M. D., et al. (2017) · Cancer Cell · doi:10.1016/j.ccell.2016.12.005 · Cited by 594 · see citing works
Self-citationFeron, O. (2009) · Radiotherapy and Oncology · doi:10.1016/j.radonc.2009.06.025 · Cited by 559 · see citing works
Inhibition of fatty acid oxidation as a therapy for MYC-overexpressing triple-negative breast cancer
Camarda, R., Zhou, A. Y., Kohnz, R. A., Balakrishnan, S., Mahieu, C. I., Anderton, B. N., Eyob, H., Kajimura, S., Tward, A. D., Krings, G., et al. (2016) · Nature Medicine · doi:10.1038/nm.4055 · Cited by 519 · see citing works
The landscape of cancer cell line metabolism
Li, H., Ning, S., Ghandi, M., Kryukov, G. V., Gopal, S., Deik, A., Souza, A., Pierce, K. A., Keskula, P., Hernandez, D., et al. (2019) · Nature Medicine · doi:10.1038/s41591-019-0404-8 · Cited by 511 · see citing works
Ireland, A. S., Micinski, A. M., Kastner, D. W., Guo, B., Wait, S. J., Spainhower, K. B., Conley, C. C., Chen, O. S., Guthrie, M. R., Soltero, D., et al. (2020) · Cancer Cell · doi:10.1016/j.ccell.2020.05.001 · Cited by 506 · see citing works
Self-citationLung Cancer: Understanding Its Molecular Pathology and the 2015 WHO Classification
Inamura, K. (2017) · Frontiers in Oncology · doi:10.3389/fonc.2017.00193 · Cited by 505 · see citing works
Gazdar, A. F., Carney, D. N., Nau, M. M., & Minna, J. D. (1985) · PubMed · Cited by 477 · see citing works
Relation between mitochondrial membrane potential and ROS formation.
Suski, J., Lebiedzińska, M., Bonora, M., Pinton, P., Duszyński, J., & Wieckowski, M. (2012) · Methods in molecular biology · doi:10.1007/978-1-61779-382-0_12 · Cited by 468 · see citing works
Regulation of cancer cell metabolism: Oncogenic MYC in the driver’s seat
Dong, Y., Tu, R., Liu, H., & Qing, G. (2020) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-020-00235-2 · Cited by 405 · see citing works
Kim, J.-W., Zeller, K. I., Wang, Y., Jegga, A. G., Aronow, B. J., O'Donnell, K. A., & Dang, C. V. (2004) · Molecular and Cellular Biology · doi:10.1128/mcb.24.13.5923-5936.2004 · Cited by 371 · see citing works
Review of aerobic glycolysis and its key enzymes – new targets for lung cancer therapy
Li, X., Gu, J., & Zhou, Q. (2014) · Thoracic Cancer · doi:10.1111/1759-7714.12148 · Cited by 331 · see citing works
Targeting metabolism to regulate immune responses in autoimmunity and cancer
Patel, C. H., Leone, R. D., Horton, M. R., & Powell, J. D. (2019) · Nature Reviews Drug Discovery · doi:10.1038/s41573-019-0032-5 · Cited by 307 · see citing works
The Influence of Metabolism on Drug Response in Cancer
Zaal, E. A., & Berkers, C. R. (2018) · Frontiers in Oncology · doi:10.3389/fonc.2018.00500 · Cited by 272 · see citing works
Johnson, B. E., Ihde, D. C., Makuch, R., Gazdar, A. F., Carney, D. N., Oie, H. K., Russell, E., Nau, M. M., & Minna, J. D. (1987) · Journal of Clinical Investigation · doi:10.1172/jci112999 · Cited by 236 · see citing works
Characterization of the cell of origin for small cell lung cancer
Park, K.-S., Liang, M., Raiser, D. M., Zamponi, R., Roach, R. R., Curtis, S. J., Walton, Z. E., Schaffer, B. E., Roake, C. M., Zmoos, A., et al. (2011) · Cell Cycle · doi:10.4161/cc.10.16.17012 · Cited by 225 · see citing works
Metabolic Diversity in Human Non-Small Cell Lung Cancer Cells
Chen, P.-H., Cai, L., Huffman, K. E., Yang, C., Kim, J., Faubert, B., Boroughs, L. K., Ko, B., Sudderth, J., McMillan, E. A., et al. (2019) · Molecular Cell · doi:10.1016/j.molcel.2019.08.028 · Cited by 206 · see citing works
Self-citationGoetzman, E. S., & Prochownik, E. V. (2018) · Frontiers in Endocrinology · doi:10.3389/fendo.2018.00129 · Cited by 199 · see citing works
Takahashi, T., Takahashi, T., Suzuki, H., et al. (1992) · Lung Cancer · doi:10.1016/0169-5002(92)90119-5 · Cited by 198 · see citing works
Inosine Monophosphate Dehydrogenase Dependence in a Subset of Small Cell Lung Cancers
Huang, F., Ni, M., Chalishazar, M. D., Huffman, K. E., Kim, J., Cai, L., Shi, X., Cai, F., Zacharias, L. G., Ireland, A. S., et al. (2018) · Cell Metabolism · doi:10.1016/j.cmet.2018.06.005 · Cited by 186 · see citing works
Self-citationSato, T., Kaneda, A., Tsuji, S., Isagawa, T., Yamamoto, S., Fujita, T., Yamanaka, R., Tanaka, Y., Nukiwa, T., Márquez, V. E., et al. (2013) · Scientific Reports · doi:10.1038/srep01911 · Cited by 177 · see citing works
MYC-Driven Small-Cell Lung Cancer is Metabolically Distinct and Vulnerable to Arginine Depletion
Chalishazar, M. D., Wait, S. J., Huang, F., Ireland, A. S., Mukhopadhyay, A., Lee, Y., Schuman, S. S., Guthrie, M. R., Berrett, K. C., Vahrenkamp, J. M., et al. (2019) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-18-4140 · Cited by 175 · see citing works
Self-citationProline Metabolism in Tumor Growth and Metastatic Progression
D’Aniello, C., Patriarca, E. J., Phang, J. M., & Minchiotti, G. (2020) · Frontiers in Oncology · doi:10.3389/fonc.2020.00776 · Cited by 165 · see citing works
Mondal, S., Roy, D., Bhattacharya, S. S., Jin, L., Jung, D., Zhang, S., Kalogera, E., Staub, J. K., Wang, Y., Xuyang, W., et al. (2018) · International Journal of Cancer · doi:10.1002/ijc.31868 · Cited by 153 · see citing works
Owonikoko, T. K., Niu, H., Nackaerts, K., et al. (2019) · Journal of Thoracic Oncology · doi:10.1016/j.jtho.2019.10.013 · Cited by 151 · see citing works
Bettencourt, I. A., & Powell, J. D. (2017) · The Journal of Immunology · doi:10.4049/jimmunol.1601318 · Cited by 104 · see citing works
Exploiting ROS and metabolic differences to kill cisplatin resistant lung cancer
Wangpaichitr, M., Wu, C., Li, Y. Y., Nguyen, D. J. M., Kandemir, H., Shah, S. S., Chen, S., Feun, L. G., Prince, J. S., Kuo, M. T., et al. (2017) · Oncotarget · doi:10.18632/oncotarget.17568 · Cited by 101 · see citing works
Cardnell, R. J., Li, L., Sen, T., Bara, R. O., Tong, P., Fujimoto, J., Ireland, A. S., Guthrie, M. R., Bheddah, S., Banerjee, U., et al. (2017) · Oncotarget · doi:10.18632/oncotarget.20621 · Cited by 88 · see citing works
Self-citationActivation of the PI3K/mTOR Pathway following PARP Inhibition in Small Cell Lung Cancer
Cardnell, R. J., Feng, Y., Mukherjee, S., Diao, L., Tong, P., Stewart, C. A., Masrorpour, F., Fan, Y.-H., Nilsson, M. B., Shen, Y., et al. (2016) · PLoS ONE · doi:10.1371/journal.pone.0152584 · Cited by 87 · see citing works
Self-citationGuanosine triphosphate links MYC-dependent metabolic and ribosome programs in small-cell lung cancer
Huang, F., Huffman, K. E., Wang, Z., Wang, X., Li, K., Cai, F., Yang, C., Cai, L., Shih, T. S., Zacharias, L. G., et al. (2020) · Journal of Clinical Investigation · doi:10.1172/jci139929 · Cited by 72 · see citing works
Self-citationExploiting metabolic vulnerabilities of Non small cell lung carcinoma
Majem, B., Nadal, E., & Muñoz‐Pinedo, C. (2019) · Seminars in Cell and Developmental Biology · doi:10.1016/j.semcdb.2019.06.004 · Cited by 54 · see citing works
Metformin partially reverses the carboplatin-resistance in NSCLC by inhibiting glucose metabolism
Liu, Y., Chun-xi, H., & Huang, X. (2017) · Oncotarget · doi:10.18632/oncotarget.20663 · Cited by 53 · see citing works
Bhattacharya, S. S., Thirusangu, P., Jin, L., Roy, D., Jung, D., Xiao, Y., Staub, J. K., Roy, B., Molina, J. R., & Shridhar, V. (2019) · Cell Death and Disease · doi:10.1038/s41419-019-1916-3 · Cited by 50 · see citing works
Targeting cisplatin-resistant human tumor cells with metabolic inhibitors
Sullivan, E. J., Kurtoğlu, M., Brenneman, R., et al. (2013) · Cancer Chemotherapy and Pharmacology · doi:10.1007/s00280-013-2366-8 · Cited by 49 · see citing works
Ying, M., Guo, C., & Hu, X. (2019) · Journal of Biological Chemistry · doi:10.1074/jbc.ra119.007841 · Cited by 45 · see citing works
drexplorer: A tool to explore dose–response relationships and drug–drug interactions
Tong, P., Coombes, K. R., Johnson, F. M., et al. (2015) · Bioinformatics · doi:10.1093/bioinformatics/btv028 · Cited by 31 · see citing works
Redman, R. A., Pohlmann, P. R., Kurman, M. R., et al. (2015) · Journal of Clinical Oncology · doi:10.1200/jco.2015.33.15_suppl.tps2606 · Cited by 30 · see citing works
MYC Expression and Metabolic Redox Changes in Cancer Cells: A Synergy Able to Induce Chemoresistance
Marengo, B., Garbarino, O., Speciale, A., Monteleone, L., Traverso, N., & Domenicotti, C. (2019) · Oxidative Medicine and Cellular Longevity · doi:10.1155/2019/7346492 · Cited by 25 · see citing works
Redman, R. A., Pohlmann, P. R., Kurman, M. R., et al. (2015) · Journal of Clinical Oncology · doi:10.1200/jco.2015.33.3_suppl.tps494 · Cited by 16 · see citing works
A Preliminary Study on Lung Cancer Prevalence Among Patients with Tuberculosis in Lesotho
Sooro, M. A., Malikelle, T., Leteka, R., Kobo, L., & Ramathebane, M. M. (2021) · Cancer Research Journal · doi:10.11648/j.crj.20210903.13 · Cited by 9 · see citing works
Genomic alterations in small cell lung cancer and their clinical relevance
Wildey, G. M., & Dowlati, A. (2016) · Translational Lung Cancer Research · doi:10.21037/tlcr.2016.07.05 · Cited by 4 · see citing works
Carter, L. (2014) · Research Explorer (The University of Manchester) · Cited by 1 · see citing works
Flagged first, then by citations
Research works printed but not linked: 2
- [1]N H, AM N, M K, D M, A B, M Y SEER Cancer Statistics Review (CSR) 1975-2016 2019 Bethesda National Cancer Institute
- [46]Berg JM, Tymoczko JL, Stryer L. The glycolytic pathway is tightly controlled. New York 2002 5th edition:[Available from: https://www.ncbi.nlm.nih.gov/books/NBK22395/.
Cited by
Sorted by citations
Shuvalov, O., Kirdeeva, Y., Fefilova, E., Netsvetay, S., Zorin, M., Vlasova, Y., Fedorova, O., Daks, A., Parfenyev, S., & Barlev, N. (2023) · Metabolites · doi:10.3390/metabo13050656 · Cited by 21 · see citing works
- Authors
- Cargill, K. R., Stewart, C. A., Park, E. M., Ramkumar, K., Gay, C. M., Cardnell, R. J., Wang, Q., Diao, L., Shen, L., Fan, Y.-H., Chan, W. K., Lorenzi, P. L., Oliver, T. G., Wang, J., & Byers, L. A.
- Affiliations
- The University of Texas MD Anderson Cancer Center (US)
- University of Utah (US)
- Corresponding author
- Byers, Lauren A.
- ORCID
- Venue
- Cancer & Metabolism
- Published
- 2021-09-23
- Volume
- 9
- Issue
- 1
- Pages
- 33-33
- ISSN
- 2049-3002 (ISSN-L)
- PMC
- PMC8461854
- OpenAlex
- W3201008556
- Cited by
- 62
- References
- 65
- Citations by year
- 2026: 10 · 2025: 14 · 2024: 11 · 2023: 17 · 2022: 10
- FWCI
- 3.78
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Cancer & Metabolism (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, other-oa)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- National Cancer Institute (P30-CA16672, R01-CA207295, U01-CA231844, U01-CA213274, U01-CA21373, T32-CA009666, R50-CA243698, S10-OD012304-01, U01-CA235510)
- International Association for the Study of Lung Cancer
- American Society of Clinical Oncology
- Andrew Sabin Family Foundation
- Abell-Hanger Foundation
- Cancer Prevention and Research Institute of Texas
- 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 › Oncology › Lung Cancer Research Studies
- Keywords
- small cell lung cancer, c-Myc, glycolysis, Warburg effect, cancer metabolism, metabolic reprogramming, oxidative phosphorylation, glucose uptake, lactic acid production, xenograft tumor growth, metabolic therapy
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