title: Adaptive Reprogramming ofDe NovoPyrimidine Synthesis Is a Metabolic Vulnerability in Triple-Negative Breast Cancer.
abstract: Chemotherapy resistance is a major barrier to the treatment of triple-negative breast cancer (TNBC), and strategies to circumvent resistance are required. Usingin vitroandin vivometabolic 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 thede novopyrimidine synthesis pathway. Pharmacologic inhibition ofde novopyrimidine synthesis sensitizes TNBC cells to genotoxic chemotherapy agents by exacerbating DNA damage. Moreover, combined treatment with doxorubicin and leflunomide, a clinically approved inhibitor of thede novopyrimidine 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 ofde novopyrimidine synthesis and show that this response can be exploited pharmacologically, using clinically approved inhibitors ofde novopyrimidine synthesis, to sensitize TNBC cells to chemotherapy.Cancer Discov; 7(4); 391-9. ©2017 AACR.See related article by Mathur et al., p. 380This article is highlighted in the In This Issue feature, p. 339.
authors.affiliation: Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts. atoker@bidmc.harvard.edu kristin.brown@petermac.org.|Cancer Center, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts.|Ludwig Center at Harvard, Harvard Medical School, Boston, Massachusetts.
authors.forename: Kristin K
authors.initials: KK
authors.lastname: Brown
authors.affiliation: Ludwig Center at Harvard, Harvard Medical School, Boston, Massachusetts.|Department of Cell Biology, Harvard Medical School, Boston, Massachusetts.
authors.forename: Jessica B
authors.initials: JB
authors.lastname: Spinelli
authors.affiliation: Cancer Center, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts.|Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts.
authors.forename: John M
authors.initials: JM
authors.lastname: Asara
authors.affiliation: Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts. atoker@bidmc.harvard.edu kristin.brown@petermac.org.|Cancer Center, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts.|Ludwig Center at Harvard, Harvard Medical School, Boston, Massachusetts.
authors.forename: Alex
authors.initials: A
authors.lastname: Toker
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D065150:Cellular Reprogramming / Q000187:drug effects; D004249:DNA Damage / Q000187:drug effects; D004317:Doxorubicin / Q000008:administration & dosage; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D005260:Female; D006801:Humans; D007555:Isoxazoles / Q000008:administration & dosage; D000077339:Leflunomide; D051379:Mice; D011743:Pyrimidines / Q000096:biosynthesis*; D064726:Triple Negative Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism*; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D007555:Isoxazoles; D011743:Pyrimidines; D004317:Doxorubicin; D000077339:Leflunomide; C030986:pyrimidine