Son, J. et al. Glutamine supports pancreatic cancer growth through a KRAS-regulated metabolic pathway. Nature 496, 101–105 (2013).
Article CAS PubMed PubMed Central Google Scholar
Lyssiotis, C. A., Son, J., Cantley, L. C. & Kimmelman, A. C. Pancreatic cancers rely on a novel glutamine metabolism pathway to maintain redox balance. Cell Cycle 12, 1987–1988 (2013).
Article CAS PubMed PubMed Central Google Scholar
Cluntun, A. A., Lukey, M. J., Cerione, R. A. & Locasale, J. W. Glutamine metabolism in cancer: understanding the heterogeneity. Trends Cancer 3, 169–180 (2017).
Article CAS PubMed PubMed Central Google Scholar
Zhang, J., Pavlova, N. N. & Thompson, C. B. Cancer cell metabolism: the essential role of the nonessential amino acid, glutamine. EMBO J. 36, 1302–1315 (2017).
Article CAS PubMed PubMed Central Google Scholar
Kamphorst, J. J. et al. Human pancreatic cancer tumors are nutrient poor and tumor cells actively scavenge extracellular protein. Cancer Res. 75, 544–553 (2015).
Article CAS PubMed PubMed Central Google Scholar
Recouvreux, M. V. et al. Glutamine depletion regulates Slug to promote EMT and metastasis in pancreatic cancer. J. Exp. Med. https://doi.org/10.1084/jem.20200388 (2020).
Lee, S. W. et al. EGFR-Pak signaling selectively regulates glutamine deprivation-induced macropinocytosis. Dev. Cell 50, 381–392.e385 (2019).
Article CAS PubMed PubMed Central Google Scholar
Luengo, A., Gui, D. Y. & Vander Heiden, M. G. Targeting metabolism for cancer therapy. Cell Chem. Biol. 24, 1161–1180 (2017).
Article CAS PubMed PubMed Central Google Scholar
Hensley, C. T., Wasti, A. T. & DeBerardinis, R. J. Glutamine and cancer: cell biology, physiology, and clinical opportunities. J. Clin. Invest. 123, 3678–3684 (2013).
Article CAS PubMed PubMed Central Google Scholar
Daye, D. & Wellen, K. E. Metabolic reprogramming in cancer: unraveling the role of glutamine in tumorigenesis. Semin. Cell Dev. Biol. 23, 362–369 (2012).
Article CAS PubMed Google Scholar
Wise, D. R. & Thompson, C. B. Glutamine addiction: a new therapeutic target in cancer. Trends Biochem. Sci. 35, 427–433 (2010).
Article CAS PubMed PubMed Central Google Scholar
Hui, S. et al. Glucose feeds the TCA cycle via circulating lactate. Nature 551, 115–118 (2017).
Article PubMed PubMed Central Google Scholar
Commisso, C. et al. Macropinocytosis of protein is an amino acid supply route in Ras-transformed cells. Nature 497, 633–637 (2013).
Article CAS PubMed PubMed Central Google Scholar
Hosios, A. M. et al. Amino acids rather than glucose account for the majority of cell mass in proliferating mammalian cells. Dev. Cell 36, 540–549 (2016).
Article CAS PubMed PubMed Central Google Scholar
Shen, Y. A. et al. Inhibition of glutaminolysis in combination with other therapies to improve cancer treatment. Curr. Opin. Chem. Biol. 62, 64–81 (2021).
Article CAS PubMed PubMed Central Google Scholar
Biancur, D. E. et al. Compensatory metabolic networks in pancreatic cancers upon perturbation of glutamine metabolism. Nat. Commun. 8, 15965 (2017).
Article CAS PubMed PubMed Central Google Scholar
Lemberg, K. M., Vornov, J. J., Rais, R. & Slusher, B. S. We’re not ‘DON’ yet: optimal dosing and prodrug delivery of 6-diazo-5-oxo-l-norleucine. Mol. Cancer Ther. 17, 1824–1832 (2018).
Article CAS PubMed PubMed Central Google Scholar
Tenora, L. et al. Tumor-targeted delivery of 6-diazo-5-oxo-l-norleucine (DON) using substituted acetylated lysine prodrugs. J. Med. Chem. 62, 3524–3538 (2019).
Article CAS PubMed PubMed Central Google Scholar
Rais, R. et al. Discovery of 6-diazo-5-oxo-l-norleucine (DON) prodrugs with enhanced CSF delivery in monkeys: a potential treatment for glioblastoma. J. Med. Chem. 59, 8621–8633 (2016).
Article CAS PubMed Google Scholar
Nedelcovych, M. T. et al. N-(pivaloyloxy)alkoxy-carbonyl prodrugs of the glutamine antagonist 6-diazo-5-oxo-l-norleucine (DON) as a potential treatment for HIV associated neurocognitive disorders. J. Med. Chem. 60, 7186–7198 (2017).
Article CAS PubMed PubMed Central Google Scholar
Hanaford, A. R. et al. Orally bioavailable glutamine antagonist prodrug JHU-083 penetrates mouse brain and suppresses the growth of MYC-driven medulloblastoma. Transl. Oncol. 12, 1314–1322 (2019).
Article PubMed PubMed Central Google Scholar
Rais, R. et al. Discovery of DRP-104, a tumor-targeted metabolic inhibitor prodrug. Sci. Adv. 8, eabq5925 (2022).
Article CAS PubMed PubMed Central Google Scholar
Leone, R. D. et al. Glutamine blockade induces divergent metabolic programs to overcome tumor immune evasion. Science 366, 1013–1021 (2019).
Article CAS PubMed PubMed Central Google Scholar
Sharma, N. S. et al. Targeting tumor-intrinsic hexosamine biosynthesis sensitizes pancreatic cancer to anti-PD1 therapy. J. Clin. Invest. 130, 451–465 (2020).
Article CAS PubMed Google Scholar
Wang, Z. et al. Targeting glutaminolysis: new perspectives to understand cancer development and novel strategies for potential target therapies. Front. Oncol. 10, 589508 (2020).
Article PubMed PubMed Central Google Scholar
Krall, A. S., Xu, S., Graeber, T. G., Braas, D. & Christofk, H. R. Asparagine promotes cancer cell proliferation through use as an amino acid exchange factor. Nat. Commun. 7, 11457 (2016).
Article CAS PubMed PubMed Central Google Scholar
Pavlova, N. N. et al. As extracellular glutamine levels decline, asparagine becomes an essential amino acid. Cell Metab. 27, 428–438.e425 (2018).
Article CAS PubMed PubMed Central Google Scholar
Pinkus, L. M. Glutamine binding sites. Methods Enzymol. 46, 414–427 (1977).
Article CAS PubMed Google Scholar
Rosenbluth, R. J., Cooney, D. A., Jayaram, H. N., Milman, H. A. & Homan, E. R. DON, CONV and DONV-II. Inhibition of l-asparagine synthetase in vivo. Biochem. Pharmacol. 25, 1851–1858 (1976).
Article CAS PubMed Google Scholar
Bayne, L. J. et al. Tumor-derived granulocyte-macrophage colony-stimulating factor regulates myeloid inflammation and T cell immunity in pancreatic cancer. Cancer Cell 21, 822–835 (2012).
Article CAS PubMed PubMed Central Google Scholar
Khanna, C. & Hunter, K. Modeling metastasis in vivo. Carcinogenesis 26, 513–523 (2005).
Article CAS PubMed Google Scholar
Bott, A. J. et al. Glutamine anabolism plays a critical role in pancreatic cancer by coupling carbon and nitrogen metabolism. Cell Rep. 29, 1287–1298.e1286 (2019).
Article CAS PubMed PubMed Central Google Scholar
Tsai, P. Y. et al. Adaptation of pancreatic cancer cells to nutrient deprivation is reversible and requires glutamine synthetase stabilization by mTORC1. Proc. Natl Acad. Sci. USA https://doi.org/10.1073/pnas.2003014118 (2021).
Balasubramanian, M. N., Butterworth, E. A. & Kilberg, M. S. Asparagine synthetase: regulation by cell stress and involvement in tumor biology. Am. J. Physiol. Endocrinol. Metab. 304, E789–E799 (2013).
Article CAS PubMed PubMed Central Google Scholar
Muller, H. J. & Boos, J. Use of l-asparaginase in childhood ALL. Crit. Rev. Oncol. Hematol. 28, 97–113 (1998).
Article CAS PubMed Google Scholar
Egler, R. A., Ahuja, S. P. & Matloub, Y. l-asparaginase in the treatment of patients with acute lymphoblastic leukemia. J. Pharmacol. Pharmacother. 7, 62–71 (2016).
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