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Zhou J, Gelot C, Pantelidou C, et al. A first-in-class Polymerase Theta Inhibitor selectively targets Homologous-Recombination-Deficient Tumors. Nat Cancer. 2021;2(6):598-610doi: 10.1038/s43018-021-00203-x.
Zhou, J., Gelot, C., Pantelidou, C., Li, A., Yücel, H., Davis, R. E., Farkkila, A., Kochupurakkal, B., Syed, A., Shapiro, G. I., Tainer, J. A., Blagg, B. S. J., Ceccaldi, R., & D'Andrea, A. D. (2021). A first-in-class Polymerase Theta Inhibitor selectively targets Homologous-Recombination-Deficient Tumors. Nature cancer, 2(6), 598-610. https://doi.org/10.1038/s43018-021-00203-x
Zhou, Jia, et al. "A first-in-class Polymerase Theta Inhibitor selectively targets Homologous-Recombination-Deficient Tumors." Nature cancer vol. 2,6 (2021): 598-610. doi: https://doi.org/10.1038/s43018-021-00203-x
Zhou J, Gelot C, Pantelidou C, Li A, Yücel H, Davis RE, Farkkila A, Kochupurakkal B, Syed A, Shapiro GI, Tainer JA, Blagg BSJ, Ceccaldi R, D'Andrea AD. A first-in-class Polymerase Theta Inhibitor selectively targets Homologous-Recombination-Deficient Tumors. Nat Cancer. 2021 Jun;2(6):598-610. doi: 10.1038/s43018-021-00203-x. Epub 2021 Jun 17. PMID: 34179826; PMCID: PMC8224818.
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Nat Cancer. 2021 Jun;2(6):598-610. doi: 10.1038/s43018-021-00203-x. Epub 2021 Jun 17.

A first-in-class Polymerase Theta Inhibitor selectively targets Homologous-Recombination-Deficient Tumors.

Nature cancer

Jia Zhou, Camille Gelot, Constantia Pantelidou, Adam Li, Hatice Yücel, Rachel E Davis, Anniina Farkkila, Bose Kochupurakkal, Aleem Syed, Geoffrey I Shapiro, John A Tainer, Brian S J Blagg, Raphael Ceccaldi, Alan D D'Andrea

Affiliations

  1. Department of Radiation Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA.
  2. Inserm U830, PSL Research University, Institut Curie, 75005, Paris, France.
  3. Department of Medical Oncology, Dana-Farber Cancer Institute and Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA.
  4. Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, IN 46556, USA.
  5. Departments of Cancer Biology and of Molecular and Cellular Oncology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
  6. Center for DNA Damage and Repair, Dana-Farber Cancer Institute, Boston, MA, USA.
  7. Susan F. Smith Center for Women's Cancers, Dana-Farber Cancer Institute, Boston, MA, USA.

PMID: 34179826 PMCID: PMC8224818 DOI: 10.1038/s43018-021-00203-x

Abstract

DNA polymerase theta (POLθ) is synthetic lethal with Homologous Recombination (HR) deficiency and thus a candidate target for HR-deficient cancers. Through high-throughput small molecule screens we identified the antibiotic Novobiocin (NVB) as a specific POLθ inhibitor that selectively kills HR-deficient tumor cells

Keywords: Fanconi Anemia; HRD cancer; Homologous Recombination; MMEJ; Novobiocin; PARP inhibitor resistance; Polymerase theta (POLθ)

References

  1. Proc Natl Acad Sci U S A. 1978 Oct;75(10):4838-42 - PubMed
  2. Genes Dev. 2017 Feb 1;31(3):318-332 - PubMed
  3. Trends Cell Biol. 2016 Jan;26(1):52-64 - PubMed
  4. Mol Cell. 2021 Apr 1;81(7):1534-1547.e4 - PubMed
  5. Nat Commun. 2019 Sep 19;10(1):4286 - PubMed
  6. N Engl J Med. 2018 Aug 23;379(8):753-763 - PubMed
  7. J Clin Oncol. 1995 May;13(5):1136-43 - PubMed
  8. DNA Repair (Amst). 2016 Aug;44:22-32 - PubMed
  9. Ann Oncol. 2018 Jun 1;29(6):1366-1376 - PubMed
  10. Mol Gen Genet. 1990 Jan;220(2):256-60 - PubMed
  11. Proc Natl Acad Sci U S A. 2010 Jul 27;107(30):13390-5 - PubMed
  12. Nature. 2016 Jul 20;535(7612):382-7 - PubMed
  13. Cancer Res. 2010 Apr 1;70(7):2984-93 - PubMed
  14. Science. 2017 Mar 17;355(6330):1152-1158 - PubMed
  15. Lancet. 2017 Oct 28;390(10106):1949-1961 - PubMed
  16. Nat Med. 2003 May;9(5):568-74 - PubMed
  17. J Med Chem. 2006 Oct 19;49(21):6177-96 - PubMed
  18. Proc Natl Acad Sci U S A. 2013 Oct 15;110(42):17041-6 - PubMed
  19. Nat Struct Mol Biol. 2017 Dec;24(12):1116-1123 - PubMed
  20. J Chem Theory Comput. 2016 Jan 12;12(1):281-96 - PubMed
  21. Nature. 2005 Apr 14;434(7035):917-21 - PubMed
  22. N Engl J Med. 2016 Dec;375(22):2154-2164 - PubMed
  23. Clin Cancer Res. 2019 Oct 15;25(20):6127-6140 - PubMed
  24. Cancer Res. 1991 Jan 15;51(2):510-3 - PubMed
  25. Nature. 2018 Aug;560(7716):122-127 - PubMed
  26. Antimicrob Agents Chemother. 1986 Jul;30(1):42-5 - PubMed
  27. Proc Natl Acad Sci U S A. 2007 Jul 17;104(29):12111-6 - PubMed
  28. PLoS Genet. 2017 May 25;13(5):e1006813 - PubMed
  29. EMBO J. 2004 Nov 10;23(22):4484-94 - PubMed
  30. Radiat Res. 2009 Aug;172(2):165-74 - PubMed
  31. Nature. 2005 Apr 14;434(7035):913-7 - PubMed
  32. Cell. 2019 Mar 7;176(6):1295-1309.e15 - PubMed
  33. Nat Med. 2013 Nov;19(11):1381-8 - PubMed
  34. N Engl J Med. 2012 Apr 12;366(15):1382-92 - PubMed
  35. Nucleic Acids Res. 2003 Nov 1;31(21):6117-26 - PubMed
  36. Crit Rev Oncol Hematol. 2016 Dec;108:73-85 - PubMed
  37. Cell. 1980 Aug;21(1):115-25 - PubMed
  38. J Biol Chem. 2004 Dec 31;279(53):55117-26 - PubMed
  39. Nature. 2015 Feb 12;518(7538):258-62 - PubMed
  40. J Biol Chem. 2018 Apr 6;293(14):5259-5269 - PubMed
  41. Clin Cancer Res. 2017 Mar 1;23(5):1263-1273 - PubMed
  42. PLoS One. 2011;6(7):e21639 - PubMed
  43. Cancer J. 2000 Jul-Aug;6(4):256-65 - PubMed
  44. Structure. 2015 Dec 1;23(12):2319-2330 - PubMed
  45. Science. 2018 Mar 16;359(6381):1217-1218 - PubMed
  46. Cancer Discov. 2019 Jun;9(6):722-737 - PubMed
  47. Mol Cell. 2018 Dec 20;72(6):925-941.e4 - PubMed
  48. NAR Cancer. 2020 Sep;2(3):zcaa013 - PubMed
  49. Nucleic Acids Res. 2018 May 4;46(8):3891-3905 - PubMed
  50. Nucleic Acids Res. 1981 Aug 11;9(15):3589-603 - PubMed
  51. Cancer Discov. 2015 Nov;5(11):1137-54 - PubMed
  52. Nat Rev Cancer. 2004 Oct;4(10):814-9 - PubMed
  53. Nature. 2015 Feb 12;518(7538):254-7 - PubMed
  54. J Chem Theory Comput. 2014 Aug 12;10(8):3207-20 - PubMed
  55. Nature. 2008 Feb 28;451(7182):1116-20 - PubMed
  56. Nature. 2018 Aug;560(7716):117-121 - PubMed
  57. PLoS Genet. 2010 Jul 01;6(7):e1001005 - PubMed
  58. Science. 2008 Oct 31;322(5902):748-50 - PubMed
  59. Nucleic Acids Res. 2014 Feb;42(3):e19 - PubMed
  60. J Biol Chem. 2000 Nov 24;275(47):37181-6 - PubMed

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