Display options
Cite
Chakrabarti G, Moore ZR, Luo X, et al. Targeting glutamine metabolism sensitizes pancreatic cancer to PARP-driven metabolic catastrophe induced by ß-lapachone. Cancer Metab. 2015;3:12doi: 10.1186/s40170-015-0137-1.
Chakrabarti, G., Moore, Z. R., Luo, X., Ilcheva, M., Ali, A., Padanad, M., Zhou, Y., Xie, Y., Burma, S., Scaglioni, P. P., Cantley, L. C., DeBerardinis, R. J., Kimmelman, A. C., Lyssiotis, C. A., & Boothman, D. A. (2015). Targeting glutamine metabolism sensitizes pancreatic cancer to PARP-driven metabolic catastrophe induced by ß-lapachone. Cancer & metabolism, 312. https://doi.org/10.1186/s40170-015-0137-1
Chakrabarti, Gaurab, et al. "Targeting glutamine metabolism sensitizes pancreatic cancer to PARP-driven metabolic catastrophe induced by ß-lapachone." Cancer & metabolism vol. 3 (2015): 12. doi: https://doi.org/10.1186/s40170-015-0137-1
Chakrabarti G, Moore ZR, Luo X, Ilcheva M, Ali A, Padanad M, Zhou Y, Xie Y, Burma S, Scaglioni PP, Cantley LC, DeBerardinis RJ, Kimmelman AC, Lyssiotis CA, Boothman DA. Targeting glutamine metabolism sensitizes pancreatic cancer to PARP-driven metabolic catastrophe induced by ß-lapachone. Cancer Metab. 2015 Oct 12;3:12. doi: 10.1186/s40170-015-0137-1. eCollection 2015. PMID: 26462257; PMCID: PMC4601138.
Copy Download .nbib Format: NLM
Share it on

Cancer Metab. 2015 Oct 12;3:12. doi: 10.1186/s40170-015-0137-1. eCollection 2015.

Targeting glutamine metabolism sensitizes pancreatic cancer to PARP-driven metabolic catastrophe induced by ß-lapachone.

Cancer & metabolism

Gaurab Chakrabarti, Zachary R Moore, Xiuquan Luo, Mariya Ilcheva, Aktar Ali, Mahesh Padanad, Yunyun Zhou, Yang Xie, Sandeep Burma, Pier P Scaglioni, Lewis C Cantley, Ralph J DeBerardinis, Alec C Kimmelman, Costas A Lyssiotis, David A Boothman

Affiliations

  1. Department of Pharmacology, University of Texas Southwestern Medical Center, 6001 Forest Park Drive, Dallas, 75390-8807 TX USA ; Radiation Oncology, University of Texas Southwestern Medical Center, Dallas, TX USA.
  2. Radiation Oncology, University of Texas Southwestern Medical Center, Dallas, TX USA.
  3. Touchstone Diabetes Center, Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX USA.
  4. Department of Internal Medicine, Weill Cornell Medical College, 413 East 69th Street, BB-1362, New York, NY 10021 USA.
  5. Department of Bioinformatics and Biostatistics, Clinical Sciences, UT Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390 USA.
  6. Department of Medicine, Weill Cornell Medical College, 413 East 69th Street, BB-1362, New York, NY 10021 USA.
  7. Children's Medical Center Research Institute, UT Southwestern Medical Center, 5323 Harry Hines Blvd, Dallas, TX 75390 USA.
  8. Department of Radiation Oncology, Division of Genomic Stability and DNA Repair, Dana-Farber Cancer Institute, Boston, MA 02215 USA.
  9. Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI 48109 USA ; Internal Medicine, Division of Gastroenterology, University of Michigan, Ann Arbor, MI 48109 USA.

PMID: 26462257 PMCID: PMC4601138 DOI: 10.1186/s40170-015-0137-1

Abstract

BACKGROUND: Pancreatic ductal adenocarcinomas (PDA) activate a glutamine-dependent pathway of cytosolic nicotinamide adenine dinucleotide phosphate (NADPH) production to maintain redox homeostasis and support proliferation. Enzymes involved in this pathway (GLS1 (mitochondrial glutaminase 1), GOT1 (cytoplasmic glutamate oxaloacetate transaminase 1), and GOT2 (mitochondrial glutamate oxaloacetate transaminase 2)) are highly upregulated in PDA, and among these, inhibitors of GLS1 were recently deployed in clinical trials to target anabolic glutamine metabolism. However, single-agent inhibition of this pathway is cytostatic and unlikely to provide durable benefit in controlling advanced disease.

RESULTS: Here, we report that reducing NADPH pools by genetically or pharmacologically (bis-2-(5-phenylacetamido-1,2,4-thiadiazol-2-yl)ethyl sulfide (BPTES) or CB-839) inhibiting glutamine metabolism in mutant Kirsten rat sarcoma viral oncogene homolog (KRAS) PDA sensitizes cell lines and tumors to ß-lapachone (ß-lap, clinical form ARQ761). ß-Lap is an NADPH:quinone oxidoreductase (NQO1)-bioactivatable drug that leads to NADPH depletion through high levels of reactive oxygen species (ROS) from the futile redox cycling of the drug and subsequently nicotinamide adenine dinucleotide (NAD)+ depletion through poly(ADP ribose) polymerase (PARP) hyperactivation. NQO1 expression is highly activated by mutant KRAS signaling. As such, ß-lap treatment concurrent with inhibition of glutamine metabolism in mutant KRAS, NQO1 overexpressing PDA leads to massive redox imbalance, extensive DNA damage, rapid PARP-mediated NAD+ consumption, and PDA cell death-features not observed in NQO1-low, wild-type KRAS expressing cells.

CONCLUSIONS: This treatment strategy illustrates proof of principle that simultaneously decreasing glutamine metabolism-dependent tumor anti-oxidant defenses and inducing supra-physiological ROS formation are tumoricidal and that this rationally designed combination strategy lowers the required doses of both agents in vitro and in vivo. The non-overlapping specificities of GLS1 inhibitors and ß-lap for PDA tumors afford high tumor selectivity, while sparing normal tissue.

Keywords: Glutamine metabolism; Metabolic cancer therapy; NQO1-bioactivated drugs; Transamination

References

  1. Cancer Metastasis Rev. 2013 Jun;32(1-2):83-107 - PubMed
  2. Mol Cell. 2010 May 28;38(4):487-99 - PubMed
  3. Front Physiol. 2013 Sep 12;4:246 - PubMed
  4. Nat Rev Drug Discov. 2014 Nov;13(11):828-51 - PubMed
  5. Mol Cancer Ther. 2014 Apr;13(4):890-901 - PubMed
  6. Proc Natl Acad Sci U S A. 2007 Jul 10;104(28):11832-7 - PubMed
  7. Cell Cycle. 2013 Jul 1;12(13):1987-8 - PubMed
  8. Appl Immunohistochem Mol Morphol. 2008 Jan;16(1):24-31 - PubMed
  9. Cancer Res. 2015 Feb 1;75(3):544-53 - PubMed
  10. Cancer Res. 2010 Nov 15;70(22):8981-7 - PubMed
  11. Antioxid Redox Signal. 2014 Jul 10;21(2):237-50 - PubMed
  12. Mol Carcinog. 2005 Aug;43(4):215-24 - PubMed
  13. J Biol Chem. 2006 Nov 3;281(44):33684-96 - PubMed
  14. Cancer Res. 2007 Jul 15;67(14 ):6936-45 - PubMed
  15. Proc Natl Acad Sci U S A. 2011 May 24;108(21):8674-9 - PubMed
  16. J Biol Chem. 2000 Feb 25;275(8):5416-24 - PubMed
  17. N Engl J Med. 2010 Apr 29;362(17):1605-17 - PubMed
  18. Cell Death Dis. 2015 Jan 15;6:e1599 - PubMed
  19. Cancer Res. 2013 Jul 15;73(14):4429-38 - PubMed
  20. Exp Hematol. 2014 Apr;42(4):247-51 - PubMed
  21. Trends Biochem Sci. 2014 Feb;39(2):91-100 - PubMed
  22. PLoS One. 2012;7(2):e31507 - PubMed
  23. Cell Metab. 2012 Jan 4;15(1):110-21 - PubMed
  24. Nature. 2009 Apr 9;458(7239):762-5 - PubMed
  25. J Med Chem. 2012 Dec 13;55(23):10551-63 - PubMed
  26. Cancer Discov. 2014 Jul;4(7):828-39 - PubMed
  27. Nat Biotechnol. 2012 Jul 10;30(7):671-8 - PubMed
  28. Cell. 2011 Mar 4;144(5):646-74 - PubMed
  29. Oncotarget. 2014 Jul 15;5(13):4722-31 - PubMed
  30. J Chromatogr B Analyt Technol Biomed Life Sci. 2008 Sep 1;872(1-2):148-53 - PubMed
  31. Biochim Biophys Acta. 2014 Jan;1837(1):51-62 - PubMed
  32. Nature. 2013 Apr 4;496(7443):101-5 - PubMed
  33. Proc Natl Acad Sci U S A. 2015 Jan 13;112(2):394-9 - PubMed
  34. Mol Cancer Ther. 2013 Oct;12 (10 ):2110-20 - PubMed
  35. Clin Cancer Res. 2011 Jan 15;17(2):275-85 - PubMed
  36. Cell. 2012 Apr 27;149(3):656-70 - PubMed
  37. Oncogene. 2015 May 14;34(20):2672-80 - PubMed
  38. J Mol Med (Berl). 2011 Mar;89(3):229-36 - PubMed
  39. Nature. 2011 Jul 06;475(7354):106-9 - PubMed
  40. Cancer Cell. 2005 May;7(5):469-83 - PubMed
  41. Cell Biol Toxicol. 2006 Mar;22(2):73-80 - PubMed

Publication Types

Grant support