Display options
Cite
Grundy M, Balakrishnan S, Fox M, et al. Genetic biomarkers predict response to dual BCL-2 and MCL-1 targeting in acute myeloid leukaemia cells. Oncotarget. 2018;9(102):37777-37789doi: 10.18632/oncotarget.26540.
Grundy, M., Balakrishnan, S., Fox, M., Seedhouse, C. H., & Russell, N. H. (2018). Genetic biomarkers predict response to dual BCL-2 and MCL-1 targeting in acute myeloid leukaemia cells. Oncotarget, 9(102), 37777-37789. https://doi.org/10.18632/oncotarget.26540
Grundy, Martin, et al. "Genetic biomarkers predict response to dual BCL-2 and MCL-1 targeting in acute myeloid leukaemia cells." Oncotarget vol. 9,102 (2018): 37777-37789. doi: https://doi.org/10.18632/oncotarget.26540
Grundy M, Balakrishnan S, Fox M, Seedhouse CH, Russell NH. Genetic biomarkers predict response to dual BCL-2 and MCL-1 targeting in acute myeloid leukaemia cells. Oncotarget. 2018 Dec 28;9(102):37777-37789. doi: 10.18632/oncotarget.26540. eCollection 2018 Dec 28. PMID: 30701031; PMCID: PMC6340871.
Copy Download .nbib Format: NLM
Share it on

Oncotarget. 2018 Dec 28;9(102):37777-37789. doi: 10.18632/oncotarget.26540. eCollection 2018 Dec 28.

Genetic biomarkers predict response to dual BCL-2 and MCL-1 targeting in acute myeloid leukaemia cells.

Oncotarget

Martin Grundy, Sahana Balakrishnan, Matthew Fox, Claire H Seedhouse, Nigel H Russell

Affiliations

  1. Clinical Haematology, Nottingham University Hospitals, Nottingham, United Kingdom.
  2. Department of Haematology, Division of Cancer and Stem Cells, University of Nottingham, Nottingham, United Kingdom.

PMID: 30701031 PMCID: PMC6340871 DOI: 10.18632/oncotarget.26540

Abstract

Acute myeloid leukaemia (AML) cells often up-regulate pro-survival members of the BCL-2 protein family, such as BCL-2 and MCL-1, to avoid apoptosis. Venetoclax (ABT-199) targets BCL-2 and has shown promising efficacy in AML but over-expression of MCL-1 can cause resistance. A co-operative approach, targeting both BCL-2 and MCL-1 may therefore prove beneficial. This study investigated the potential synergistic relationship between Venetoclax and the MCL-1 inhibitor S63845 in AML cells. We treated MV4-11 cells and primary AML samples for 4 hours with Venetoclax, S63845 or the combination. We used a short-term flow cytometric technique to assess synergy using cytochrome C release as a read out of response. The combination of Venetoclax and S63845 produced a synergistic apoptotic response in MV4-11 cells and primary samples, including the leukaemia re-populating leukaemic stem cell (LSC) population, in 92% of the samples. Known molecular biomarkers of response to BCL-2 and MCL-1 targeting agents were corroborated, and augmented, with the short-term functional assay. The assay also predicted potential biomarkers of response to the combination of BCL-2 and MCL-1 targeting agents. Primary samples with an IDH2_140 mutation were more sensitive to Venetoclax as a single agent whereas samples with a FLT3-ITD mutation were more resistant. This resistance could be reversed when combined with S63845. All FLT3-ITD and NPM1 mutated samples were sensitive to the combination of drugs. We report that co-operatively targeting BCL-2 and MCL-1 may be beneficial in AML and a short-term

Keywords: AML; BCL-2; MCL-1; S63845; Venetoclax

Conflict of interest statement

CONFLICTS OF INTEREST The authors declare no conflicts of interest.

References

  1. Br J Haematol. 2003 Mar;120(6):1009-16 - PubMed
  2. Br J Haematol. 2009 Dec;147(5):653-61 - PubMed
  3. Blood. 2009 Dec 3;114(24):5034-43 - PubMed
  4. Blood. 2010 Feb 18;115(7):1425-32 - PubMed
  5. Blood. 2011 Mar 31;117(13):3696-7 - PubMed
  6. Blood. 2011 Jul 14;118(2):409-12 - PubMed
  7. J Clin Oncol. 2011 Aug 20;29(24):3328-30 - PubMed
  8. J Clin Oncol. 2012 Feb 10;30(5):488-96 - PubMed
  9. N Engl J Med. 2012 Mar 22;366(12):1079-89 - PubMed
  10. J Biol Chem. 2013 Feb 8;288(6):3804-15 - PubMed
  11. Cell Stem Cell. 2013 Mar 7;12(3):329-41 - PubMed
  12. Methods. 2013 Jun 1;61(2):156-64 - PubMed
  13. Genes Dev. 2013 Jun 15;27(12):1351-64 - PubMed
  14. J Biomol Screen. 2014 Jun;19(5):817-21 - PubMed
  15. ACS Chem Biol. 2014 Sep 19;9(9):1962-8 - PubMed
  16. Haematologica. 2014 Aug;99(8):1277-84 - PubMed
  17. Nat Med. 2015 Feb;21(2):178-84 - PubMed
  18. Cell. 2015 Feb 26;160(5):977-989 - PubMed
  19. FEBS J. 2016 Jul;283(14):2661-75 - PubMed
  20. Blood. 2016 Jun 23;127(25):3215-24 - PubMed
  21. Oncotarget. 2017 Mar 7;8(10):16220-16232 - PubMed
  22. Clin Cancer Res. 2016 Sep 1;22(17):4440-51 - PubMed
  23. Cancer Cell. 2016 Jul 11;30(1):92-107 - PubMed
  24. Cancer Discov. 2016 Oct;6(10):1106-1117 - PubMed
  25. Nature. 2016 Oct 27;538(7626):477-482 - PubMed
  26. Blood. 2017 Jan 26;129(4):424-447 - PubMed
  27. Leuk Lymphoma. 2017 Sep;58(9):1-17 - PubMed
  28. Leukemia. 2018 Feb;32(2):303-312 - PubMed
  29. Sci Transl Med. 2017 Aug 2;9(401):null - PubMed
  30. Blood. 2017 Dec 7;130(23):2469-2474 - PubMed
  31. Signal Transduct Target Ther. 2017 Apr 07;2:17012 - PubMed
  32. PLoS One. 2018 Jan 3;13(1):e0190682 - PubMed
  33. Lancet Oncol. 2018 Feb;19(2):216-228 - PubMed
  34. Leuk Lymphoma. 2018 Oct;59(10):2447-2453 - PubMed
  35. J Clin Oncol. 2018 Jul 1;36(19):1973-1980 - PubMed
  36. PLoS One. 2018 May 3;13(5):e0196805 - PubMed
  37. Front Med. 2018 Oct;12(5):593-599 - PubMed
  38. Clin Cancer Res. 2018 Sep 15;24(18):4371-4379 - PubMed
  39. Leukemia. 2019 Jan;33(1):262-266 - PubMed
  40. Blood. 2018 Sep 6;132(10):1007-1012 - PubMed
  41. Leukemia. 2018 Sep 10;:null - PubMed
  42. Blood. 2019 Jan 3;133(1):7-17 - PubMed
  43. Blood. 1993 Jun 1;81(11):3091-6 - PubMed
  44. Oncogene. 1995 Jun 1;10(11):2207-12 - PubMed
  45. J Cell Biol. 1995 Mar;128(6):1173-84 - PubMed
  46. Antisense Res Dev. 1993 Summer;3(2):157-69 - PubMed
  47. Blood. 1998 Feb 1;91(3):991-1000 - PubMed

Publication Types