Adaptive Reprogramming of De Novo Pyrimidine Synthesis Is a Metabolic Vulnerability in Triple-Negative Breast Cancer
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Abstract
Chemotherapy resistance is a major barrier to the treatment of triple-negative breast cancer (TNBC), and strategies to circumvent resistance are required. Using in vitro and in vivo metabolic profiling of TNBC cells, we show that an increase in the abundance of pyrimidine nucleotides occurs in response to chemotherapy exposure. Mechanistically, elevation of pyrimidine nucleotides induced by chemotherapy is dependent on increased activity of the de novo pyrimidine synthesis pathway. Pharmacologic inhibition of de novo pyrimidine synthesis sensitizes TNBC cells to genotoxic chemotherapy agents by exacerbating DNA damage. Moreover, combined treatment with doxorubicin and leflunomide, a clinically approved inhibitor of the de novo pyrimidine synthesis pathway, induces regression of TNBC xenografts. Thus, the increase in pyrimidine nucleotide levels observed following chemotherapy exposure represents a metabolic vulnerability that can be exploited to enhance the efficacy of chemotherapy for the treatment of TNBC. Significance: The prognosis for patients with TNBC with residual disease after chemotherapy is poor. We find that chemotherapy agents induce adaptive reprogramming of de novo pyrimidine synthesis and show that this response can be exploited pharmacologically, using clinically approved inhibitors of de novo pyrimidine synthesis, to sensitize TNBC cells to chemotherapy. Cancer Discov; 7(4); 391–9. ©2017 AACR. See related article by Mathur et al., p. 380. This article is highlighted in the In This Issue feature, p. 339
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Inducing DNA damage with genotoxic chemotherapies can sensitize cells to inhibitors of nucleotide biosynthesis.
“Inducing DNA damage with the use of genotoxic chemotherapies can sensitize cells to inhibitors of nucleotide biosynthesis (Brown et al., 2017; Peters et al., 2000), suggesting that oncogenic mutations that reduce the DNA damage response is one explanation for why a therapeutic window exists for antimetabolite compounds.”
From Targeting Metabolism for Cancer Therapy (2017) · cites this paper as Brown et al., 2017
DHODH activity is elevated in response to DNA damage and upon genotoxic chemotherapy treatment to increase nucleotide synthesis for DNA repair.
“DHODH activity is also elevated in response to DNA damage and upon genotoxic chemotherapy treatment to increase nucleotide synthesis for DNA repair.76,77”
From The multifaceted contributions of mitochondria to cellular metabolism (2018) · cites this paper as [77]
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Cites
Hallmarks of Cancer: The Next Generation
Hanahan, D., & Weinberg, R. A. (2011) · Cell · doi:10.1016/j.cell.2011.02.013 · Cited by 66,590 · see citing works
Cortazar, P., Zhang, L., Untch, M., Mehta, K. M., Costantino, J. P., Wolmark, N., Bonnefoi, H. R., Cameron, D., Gianni, L., Valagussa, P., et al. (2014) · The Lancet · doi:10.1016/s0140-6736(13)62422-8 · Cited by 4,777 · see citing works
Metabolic Reprogramming: A Cancer Hallmark Even Warburg Did Not Anticipate
Ward, P. S., & Thompson, C. B. (2012) · Cancer Cell · doi:10.1016/j.ccr.2012.02.014 · Cited by 3,233 · see citing works
Liedtke, C., Mazouni, C., Hess, K. R., André, F., Tordai, A., Mejia, J. A., Symmans, W. F., Gonzalez-Angulo, A. M., Hennessy, B., Green, M., et al. (2008) · Journal of Clinical Oncology · doi:10.1200/jco.2007.14.4147 · Cited by 2,892 · see citing works
Kuerer, H. M., Newman, L. A., Smith, T. L., Ames, F. C., Hunt, K. K., Dhingra, K., Theriault, R. L., Singh, G., Binkley, S. M., Sneige, N., et al. (1999) · Journal of Clinical Oncology · doi:10.1200/jco.1999.17.2.460 · Cited by 1,329 · see citing works
Efficacy of Neoadjuvant Cisplatin in Triple-Negative Breast Cancer
Silver, D. P., Richardson, A. L., Eklund, A. C., Wang, Z. C., Szállási, Z., Li, Q., Birkbak, N. J., Leong, C.-O., Calogrias, D., Buraimoh, A., et al. (2010) · Journal of Clinical Oncology · doi:10.1200/jco.2009.22.4725 · Cited by 982 · see citing works
Masuda, H., Baggerly, K., Wang, Y., Zhang, Y., Gonzalez-Angulo, A. M., Meric‐Bernstam, F., Valero, V., Lehmann, B. D., Pietenpol, J. A., Hortobágyi, G. N., et al. (2013) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-13-0799 · Cited by 753 · see citing works
Stimulation of de novo pyrimidine synthesis by growth signaling through mTOR and S6K1
Ben-Sahra, I., Howell, J. J., Asara, J. M., & Manning, B. D. (2013) · Science · doi:10.1126/science.1228792 · Cited by 739 · see citing works
Self-citationMetabolic targets for cancer therapy
Galluzzi, L., Kepp, O., Heiden, M. G. V., & Kroemer, G. (2013) · Nature Reviews Drug Discovery · doi:10.1038/nrd4145 · Cited by 705 · see citing works
Guarneri, V., Broglio, K. R., Kau, S., Cristofanilli, M., Buzdar, A. U., Valero, V., Buchholz, T. A., Meric, F., Middleton, L. P., Hortobágyi, G. N., et al. (2006) · Journal of Clinical Oncology · doi:10.1200/jco.2005.02.6914 · Cited by 600 · see citing works
Quantitative Phosphoproteomics Reveal mTORC1 Activates de Novo Pyrimidine Synthesis
Robitaille, A. M., Christen, S., Shimobayashi, M., Cornu, M., Fava, L. L., Moes, S., Prescianotto-Baschong, C., Sauer, U., Jenoe, P., & Hall, M. N. (2013) · Science · doi:10.1126/science.1228771 · Cited by 525 · see citing works
DHODH modulates transcriptional elongation in the neural crest and melanoma
White, R. M., Cech, J. N., Ratanasirintrawoot, S., Lin, C. Y., Rahl, P. B., Burke, C. J., Langdon, E. M., Tomlinson, M. L., Mosher, J. T., Kaufman, C. K., et al. (2011) · Nature · doi:10.1038/nature09882 · Cited by 452 · see citing works
Jeong, S. M., Xiao, C., Finley, L. W. S., Lahusen, T., Souza, A. L., Pierce, K., Li, Y.-H., Wang, X., Laurent, G., German, N. J., et al. (2013) · Cancer Cell · doi:10.1016/j.ccr.2013.02.024 · Cited by 445 · see citing works
ATM activates the pentose phosphate pathway promoting anti‐oxidant defence and DNA repair
Cosentino, C., Grieco, D., & Costanzo, V. (2010) · The EMBO Journal · doi:10.1038/emboj.2010.330 · Cited by 436 · see citing works
Regulation of carbamoyl phosphate synthetase by MAP kinase
Graves, L. M., Guy, H. I., Kozlowski, P., Huang, M., Lazarowski, E. R., Pope, R. M., Collins, M. A., Dahlstrand, E. N., Earp, H. S., & Evans, D. R. (2000) · Nature · doi:10.1038/35002111 · Cited by 232 · see citing works
Inhibitors of de Novo Nucleotide Biosynthesis as Drugs
Christopherson, R. I., Lyons, S. D., & Wilson, P. K. (2002) · Accounts of Chemical Research · doi:10.1021/ar0000509 · Cited by 163 · see citing works
ATM Couples Replication Stress and Metabolic Reprogramming during Cellular Senescence
Aird, K. M., Worth, A. J., Snyder, N. W., Lee, J. V., Sivanand, S., Liu, Q., Blair, I. A., Wellen, K. E., & Zhang, R. (2015) · Cell Reports · doi:10.1016/j.celrep.2015.04.014 · Cited by 113 · see citing works
Fragoso, Y. D., & Brooks, J. B. B. (2015) · Expert Review of Clinical Pharmacology · doi:10.1586/17512433.2015.1019343 · Cited by 97 · see citing works
Wilson, P. M., LaBonte, M. J., Russell, J., Louie, S. G., Ghobrial, A. A., & Ladner, R. D. (2011) · Nucleic Acids Research · doi:10.1093/nar/gkr350 · Cited by 89 · see citing works
Zhang, L., Mizumoto, K., Sato, N., Ogawa, T., Kusumoto, M., Niiyama, H., & Tanaka, M. (1999) · Cancer Letters · doi:10.1016/s0304-3835(99)00107-x · Cited by 81 · see citing works
Sigoillot, F. D., Evans, D. R., & Guy, H. I. (2002) · Journal of Biological Chemistry · doi:10.1074/jbc.m201112200 · Cited by 40 · see citing works
Strawn, L. M., Kabbinavar, F. F., Schwartz, D. P., et al. (2000) · PubMed · Cited by 21 · see citing works
Wadler, S., Mao, X., Bajaj, R., et al. (1993) · Molecular Pharmacology · doi:10.1016/s0026-895x(25)13277-x · Cited by 8 · see citing works
Flagged first, then by citations
Research works printed but not linked: 2
- [1]Isakoff SJ Triple-negative breast cancer: role of specific chemotherapy agents Cancer J 2010 16 53 61 20164691 PMC2882502
- [18]Collins KD Stark GR Aspartate transcarbamylase. Interaction with the transition state analogue N-(phosphonacetyl)-L-aspartate J Biol Chem 1971 246 6599 6605 4943676
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Spinelli, J. B., & Haigis, M. C. (2018) · Nature Cell Biology · doi:10.1038/s41556-018-0124-1 · Cited by 1,935 · see citing works
Self-citationTargeting Metabolism for Cancer Therapy
Luengo, A., Gui, D. Y., & Vander Heiden, M. G. (2017) · Cell Chemical Biology · doi:10.1016/j.chembiol.2017.08.028 · Cited by 971 · see citing works
Drug repurposing for cancer therapy
Xia, Y., Sun, M., Huang, H., & Jin, W.-L. (2024) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-024-01808-1 · Cited by 443 · see citing works
“105,106 In addition, Yamaguchi and colleagues proposed that le fl unomide-mediated pyrimidine synthesis could be a therapeutic target for mitigating the metastatic progression of CRC.”
BackgroundNuclear Acetyl-CoA Production by ACLY Promotes Homologous Recombination
Sivanand, S., Rhoades, S., Jiang, Q., Lee, J. V., Benci, J., Zhang, J., Yuan, S., Viney, I., Zhao, S., Carrer, A., et al. (2017) · Molecular Cell · doi:10.1016/j.molcel.2017.06.008 · Cited by 295 · see citing works
Oncogenic KRAS supports pancreatic cancer through regulation of nucleotide synthesis
Santana-Codina, N., Roeth, A. A., Zhang, Y., Yang, A., Mashadova, O., Asara, J. M., Wang, X., Bronson, R. T., Lyssiotis, C. A., Ying, H., et al. (2018) · Nature Communications · doi:10.1038/s41467-018-07472-8 · Cited by 252 · see citing works
Self-citationMetabolic reprogramming in triple-negative breast cancer
Wang, Z., Jiang, Q., & Dong, C. (2020) · Cancer Biology and Medicine · doi:10.20892/j.issn.2095-3941.2019.0210 · Cited by 248 · see citing works
“Exposure to doxorubicin likely stimulates pyrimidine synthesis by regulating the post-translational modification of CAD and its activity, whereas inhibiting DHODH sensitizes TNBC cells to doxorubicin and significantly induces the regression of TNBC xenografts 115 .”
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Spinelli, J. B., Rosen, P. C., Sprenger, H.-G., Puszynska, A. M., Mann, J. L., Roessler, J. M., Cangelosi, A. L., Henne, A., Condon, K. J., Zhang, T., et al. (2021) · Science · doi:10.1126/science.abi7495 · Cited by 221 · see citing works
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The role of ASCT2 in cancer: A review
Liu, Y., Zhao, T., Li, Z., Wang, L., Yuan, S., & Sun, L. (2018) · European Journal of Pharmacology · doi:10.1016/j.ejphar.2018.07.007 · Cited by 162 · see citing works
Cleavage of CAD by caspase-3 determines the cancer cell fate during chemotherapy
Ma, J., Zhao, J., Zhang, C., Tan, J., Cheng, A., Niu, Z., Lin, Z., Pan, G., Chen, C., Ding, Y., et al. (2025) · Nature Communications · doi:10.1038/s41467-025-60144-2 · Cited by 14 · see citing works
- Authors
- Brown, K. K., Spinelli, J. B., Asara, J. M., & Toker, A.
- Affiliations
- Beth Israel Deaconess Medical Center (US)
- Harvard University (US)
- Corresponding author
- Brown, Kristin K.
- Toker, Alex
- Venue
- Cancer Discovery
- Published
- 2017-04-01
- Volume
- 7
- Issue
- 4
- Pages
- 391-399
- ISSN
- 2159-8274 (ISSN-L)
- 2159-8290
- PMC
- PMC5380483
- OpenAlex
- W2592487518
- Cited by
- 198
- References
- 23
- Citations by year
- 2026: 11 · 2025: 20 · 2024: 23 · 2023: 20 · 2022: 23 · 2021: 29 · 2020: 31 · 2019: 13 · 2018: 20 · 2017: 7
- FWCI
- 8.05
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Cancer Discovery (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Cancer Institute (R01CA200671)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Biochemical and Molecular Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Lipids, and Metabolism
- Keywords
- triple-negative breast cancer, de novo pyrimidine biosynthesis, pyrimidine nucleotides, chemoresistance, metabolic vulnerability, leflunomide, doxorubicin, DNA damage, metabolic reprogramming
- MeSH terms
- Leflunomide, Animals, Antineoplastic Agents, Antineoplastic Combined Chemotherapy Protocols, DNA Damage, Doxorubicin, Female, Humans, Isoxazoles, Pyrimidines, Apoptosis, Drug Resistance, Neoplasm, Xenograft Model Antitumor Assays, Cell Line, Tumor, Mice, Triple Negative Breast Neoplasms, Cellular Reprogramming
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