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The Role of BCL-2/MCL-1 Targeting in Acute Myeloid Leukemia

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Pathogenesis and Treatment of Leukemia

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Abstract

The B cell lymphoma-2 (BCL-2) family of proteins plays a critical role in the intrinsic pathway of apoptosis. It is therefore not surprising that this pathway is frequently dysregulated in numerous malignancies, including acute myeloid leukemia (AML), in order to evade apoptosis. In the last 25 years, research into the pathobiology of AML has focused intensely on the antiapoptotic proteins, BCL-2, and myeloid cell leukemia-1 (MCL-1), whose overexpressions are associated with enhanced survival and chemoresistance of leukemic cells. In light of this, BCL-2 and MCL-1 have been attractive targets in the development of novel agents to treat AML. Many BCL-2 and MCL-1 inhibitors have yielded promising results in preclinical trials and are currently undergoing evaluation in clinical trials. Recently, venetoclax, a first-in-class selective oral BCL-2 inhibitor, was approved for upfront treatment of AML in the unfit or elderly population and had revolutionized the therapeutic landscape of AML. In this chapter, we will review the role of BCL-2 and MCL-1 in AML as well as the preclinical and clinical data supporting the use of BCL-2 and MCL-1 inhibitors in AML treatment. Furthermore, we will discuss the mechanisms of resistance to BCL-2 inhibitors and highlight ongoing clinical trials of combination therapies aimed at overcoming such resistance pathways.

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References

  1. Czabotar PE, Lessene G, Strasser A, Adams JM. Control of apoptosis by the BCL-2 protein family: implications for physiology and therapy. Nat Rev Mol Cell Biol. 2014;15(1):49–63.

    CAS  PubMed  Google Scholar 

  2. Fulda S, Debatin KM. Extrinsic versus intrinsic apoptosis pathways in anticancer chemotherapy. Oncogene. 2006;25(34):4798–811.

    CAS  PubMed  Google Scholar 

  3. Kollek M, Müller A, Egle A, Erlacher M. Bcl-2 proteins in development, health, and disease of the hematopoietic system. FEBS J. 2016;283(15):2779–810.

    CAS  PubMed  Google Scholar 

  4. Vaux DL, Cory S, Adams JM. Bcl-2 gene promotes haemopoietic cell survival and cooperates with c-myc to immortalize pre-B cells. Nature. 1988;335(6189):440–2.

    CAS  PubMed  Google Scholar 

  5. Russell NH, Hunter AE, Bradbury D, Zhu YM, Keith F. Biological features of leukaemic cells associated with autonomous growth and reduced survival in acute myeloblastic leukaemia. Leuk Lymphoma. 1995;16(3–4):223–9.

    CAS  PubMed  Google Scholar 

  6. Delia D, Aiello A, Soligo D, Fontanella E, Melani C, Pezzella F, et al. Bcl-2 proto-oncogene expression in normal and neoplastic human myeloid cells. Blood. 1992;79(5):1291–8.

    CAS  PubMed  Google Scholar 

  7. Campos L, Rouault JP, Sabido O, Oriol P, Roubi N, Vasselon C, et al. High expression of bcl-2 protein in acute myeloid leukemia cells is associated with poor response to chemotherapy. Blood. 1993;81(11):3091–6.

    CAS  PubMed  Google Scholar 

  8. Lagadinou ED, Sach A, Callahan K, Rossi RM, Neering SJ, Minhajuddin M, et al. BCL-2 inhibition targets oxidative phosphorylation and selectively eradicates quiescent human leukemia stem cells. Cell Stem Cell. 2013;12(3):329–41.

    CAS  PubMed  PubMed Central  Google Scholar 

  9. Campos L, Sabido O, Rouault J, Guyotat D. Effects of BCL-2 antisense oligodeoxynucleotides on in vitro proliferation and survival of normal marrow progenitors and leukemic cells. Blood. 1994;84(2):595–600.

    CAS  PubMed  Google Scholar 

  10. Cotter FE, Johnson P, Hall P, Pocock C, Al Mahdi N, Cowell JK, et al. Antisense oligonucleotides suppress B-cell lymphoma growth in a SCID-hu mouse model. Oncogene. 1994;9(10):3049–55.

    CAS  PubMed  Google Scholar 

  11. Marcucci G, Byrd JC, Dai G, Klisovic MI, Kourlas PJ, Young DC, et al. Phase 1 and pharmacodynamic studies of G3139, a Bcl-2 antisense oligonucleotide, in combination with chemotherapy in refractory or relapsed acute leukemia. Blood. 2003;101(2):425–32.

    CAS  PubMed  Google Scholar 

  12. Marcucci G, Stock W, Dai G, Klisovic RB, Liu S, Klisovic MI, et al. Phase I study of oblimersen sodium, an antisense to Bcl-2, in untreated older patients with acute myeloid leukemia: pharmacokinetics, pharmacodynamics, and clinical activity. J Clin Oncol. 2005;23(15):3404–11.

    CAS  PubMed  Google Scholar 

  13. Marcucci G, Moser B, Blum W, Stock W, Wetzler M, Kolitz JE, et al. A phase III randomized trial of intensive induction and consolidation chemotherapy ± oblimersen, a pro-apoptotic Bcl-2 antisense oligonucleotide in untreated acute myeloid leukemia patients >60 years old. J Clin Oncol. 2007;25(18_Suppl):7012.

    Google Scholar 

  14. Nguyen M, Marcellus RC, Roulston A, Watson M, Serfass L, Murthy Madiraju SR, et al. Small molecule obatoclax (GX15-070) antagonizes MCL-1 and overcomes MCL-1-mediated resistance to apoptosis. Proc Natl Acad Sci. 2007;104(49):19512–7.

    CAS  PubMed  PubMed Central  Google Scholar 

  15. Konopleva M, Watt J, Contractor R, Tsao T, Harris D, Estrov Z, et al. Mechanisms of antileukemic activity of the novel Bcl-2 homology Domain-3 mimetic GX15-070 (obatoclax). Cancer Res. 2008;68(9):3413–20.

    CAS  PubMed  PubMed Central  Google Scholar 

  16. Schimmer AD, O’Brien S, Kantarjian H, Brandwein J, Cheson BD, Minden MD, et al. A phase I study of the pan bcl-2 family inhibitor obatoclax mesylate in patients with advanced hematologic malignancies. Clin Cancer Res. 2008;14(24):8295–301.

    CAS  PubMed  Google Scholar 

  17. Schimmer AD, Raza A, Carter TH, Claxton D, Erba H, DeAngelo DJ, et al. A multicenter Phase I/II study of obatoclax mesylate administered as a 3- or 24-hour infusion in older patients with previously untreated acute myeloid leukemia. PLoS One. 2014;9(10):e108694.

    PubMed  PubMed Central  Google Scholar 

  18. Konopleva M, Contractor R, Tsao T, Samudio I, Ruvolo PP, Kitada S, et al. Mechanisms of apoptosis sensitivity and resistance to the BH3 mimetic ABT-737 in acute myeloid leukemia. Cancer Cell. 2006;10(5):375–88.

    CAS  PubMed  Google Scholar 

  19. van Delft MF, Wei AH, Mason KD, Vandenberg CJ, Chen L, Czabotar PE, et al. The BH3 mimetic ABT-737 targets selective Bcl-2 proteins and efficiently induces apoptosis via Bak/Bax if mcl-1 is neutralized. Cancer Cell. 2006;10(5):389–99.

    PubMed  PubMed Central  Google Scholar 

  20. Tse C, Shoemaker AR, Adickes J, Anderson MG, Chen J, Jin S, et al. ABT-263: a potent and orally bioavailable Bcl-2 family inhibitor. Cancer Res. 2008;68(9):3421–8.

    CAS  PubMed  Google Scholar 

  21. Knorr KLB, Schneider PA, Meng XW, Dai H, Smith BD, Hess AD, et al. MLN4924 induces Noxa upregulation in acute myelogenous leukemia and synergizes with Bcl-2 inhibitors. Cell Death Differ. 2015;22(12):2133–42.

    CAS  PubMed  PubMed Central  Google Scholar 

  22. Airiau K, Prouzet-Mauléon V, Rousseau B, Pigneux A, Jeanneteau M, Giraudon M, et al. Synergistic cooperation between ABT-263 and MEK1/2 inhibitor: effect on apoptosis and proliferation of acute myeloid leukemia cells. Oncotarget. 2015;7(1):845–59.

    PubMed Central  Google Scholar 

  23. Kontro M, Kumar A, Majumder MM, Eldfors S, Parsons A, Pemovska T, et al. HOX gene expression predicts response to BCL-2 inhibition in acute myeloid leukemia. Leukemia. 2017;31(2):301–9.

    CAS  PubMed  Google Scholar 

  24. Kivioja JL, Thanasopoulou A, Kumar A, Kontro M, Yadav B, Majumder MM, et al. Dasatinib and navitoclax act synergistically to target NUP98-NSD1+/FLT3-ITD+ acute myeloid leukemia. Leukemia. 2019;33(6):1360–72.

    CAS  PubMed  Google Scholar 

  25. Souers AJ, Leverson JD, Boghaert ER, Ackler SL, Catron ND, Chen J, et al. ABT-199, a potent and selective BCL-2 inhibitor, achieves antitumor activity while sparing platelets. Nat Med. 2013;19(2):202–8.

    CAS  PubMed  Google Scholar 

  26. Pan R, Hogdal LJ, Benito JM, Bucci D, Han L, Borthakur G, et al. Selective BCL-2 inhibition by ABT-199 causes on-target cell death in acute myeloid leukemia. Cancer Discov. 2014;4(3):362–75.

    CAS  PubMed  Google Scholar 

  27. Leverson JD, Phillips DC, Mitten MJ, Boghaert ER, Diaz D, Tahir SK, et al. Exploiting selective BCL-2 family inhibitors to dissect cell survival dependencies and define improved strategies for cancer therapy. Sci Transl Med. 2015;7(279):279ra40.

    PubMed  Google Scholar 

  28. Roberts AW, Seymour JF, Brown JR, Wierda WG, Kipps TJ, Khaw SL, et al. Substantial susceptibility of chronic lymphocytic leukemia to BCL2 inhibition: results of a phase I study of navitoclax in patients with relapsed or refractory disease. J Clin Oncol. 2012;30(5):488–96.

    CAS  PubMed  Google Scholar 

  29. Konopleva M, Pollyea DA, Potluri J, Chyla B, Hogdal L, Busman T, et al. Efficacy and biological correlates of response in a phase II study of venetoclax monotherapy in patients with acute myelogenous leukemia. Cancer Discov. 2016;6(10):1106–17.

    CAS  PubMed  PubMed Central  Google Scholar 

  30. Chan SM, Thomas D, Corces-Zimmerman MR, Xavy S, Rastogi S, Hong W-J, et al. Isocitrate dehydrogenase 1 and 2 mutations induce BCL-2 dependence in acute myeloid leukemia. Nat Med. 2015;21(2):178–84.

    CAS  PubMed  PubMed Central  Google Scholar 

  31. Appelbaum FR, Gundacker H, Head DR, Slovak ML, Willman CL, Godwin JE, et al. Age and acute myeloid leukemia. Blood. 2006;107(9):3481–5.

    CAS  PubMed  PubMed Central  Google Scholar 

  32. Pinto A, Zagonel V, Ferrara F. Acute myeloid leukemia in the elderly: biology and therapeutic strategies. Crit Rev Oncol Hematol. 2001;39(3):275–87.

    CAS  PubMed  Google Scholar 

  33. Bogenberger JM, Kornblau SM, Pierceall WE, Lena R, Chow D, Shi CX, et al. BCL-2 family proteins as 5-Azacytidine-sensitizing targets and determinants of response in myeloid malignancies. Leukemia. 2014;28(8):1657–65.

    CAS  PubMed  PubMed Central  Google Scholar 

  34. Pollyea DA, Pratz KW, Jonas BA, Letai A, Pullarkat VA, Wei A, et al. Venetoclax in combination with hypomethylating agents induces rapid, deep, and durable responses in patients with AML ineligible for intensive therapy. Blood. 2018;132(Suppl 1):285.

    Google Scholar 

  35. DiNardo CD, Pratz K, Pullarkat V, Jonas BA, Arellano M, Becker PS, et al. Venetoclax combined with decitabine or azacitidine in treatment-naive, elderly patients with acute myeloid leukemia. Blood. 2019;133(1):7–17.

    CAS  PubMed  PubMed Central  Google Scholar 

  36. DiNardo CD, Jonas BA, Pullarkat V, Thirman MJ, Garcia JS, Wei AH, et al. Azacitidine and Venetoclax in previously untreated acute myeloid leukemia. N Engl J Med. 2020;383(7):617–29.

    CAS  PubMed  Google Scholar 

  37. Wei AH, Strickland SA Jr, Hou JZ, Fiedler W, Lin TL, Walter RB, et al. Venetoclax combined with low-dose cytarabine for previously untreated patients with acute myeloid leukemia: results from a phase Ib/II study. J Clin Oncol. 2019;37(15):1277–84.

    CAS  PubMed  PubMed Central  Google Scholar 

  38. Teh TC, Nguyen NY, Moujalled DM, Segal D, Pomilio G, Rijal S, et al. Enhancing venetoclax activity in acute myeloid leukemia by co-targeting MCL1. Leukemia. 2018;32(2):303–12.

    CAS  PubMed  Google Scholar 

  39. Niu X, Zhao J, Ma J, Xie C, Edwards H, Wang G, et al. Binding of released Bim to mcl-1 is a mechanism of intrinsic resistance to ABT-199 which can be overcome by combination with daunorubicin or cytarabine in AML cells. Clin Cancer Res. 2016;22(17):4440–51.

    CAS  PubMed  PubMed Central  Google Scholar 

  40. Wei AH, Montesinos P, Ivanov V, DiNardo CD, Novak J, Laribi K, et al. Venetoclax plus LDAC for newly diagnosed AML ineligible for intensive chemotherapy: a phase 3 randomized placebo-controlled trial. Blood. 2020;135(24):2137–45.

    CAS  PubMed  PubMed Central  Google Scholar 

  41. Ibrahim A, Dongyun Y, Ahmed A, Haris A, Karamjeet S, Monzr MAM, et al. Efficacy of the combination of venetoclax and hypomethylating agents in relapsed/refractory acute myeloid leukemia. Haematologica. 2018;103(9):e404–e7.

    Google Scholar 

  42. Goldberg AD, Horvat TZ, Hsu M, Devlin SM, Cuello BM, Daley RJ, et al. Venetoclax combined with either a hypomethylating agent or low-dose cytarabine shows activity in relapsed and refractory myeloid malignancies. Blood. 2017;130(Suppl 1):1353.

    Google Scholar 

  43. DiNardo CD, Rausch CR, Benton C, Kadia T, Jain N, Pemmaraju N, et al. Clinical experience with the BCL2-inhibitor venetoclax in combination therapy for relapsed and refractory acute myeloid leukemia and related myeloid malignancies. Am J Hematol. 2018;93(3):401–7.

    CAS  PubMed  Google Scholar 

  44. Kantarjian HM, DiNardo CD, Nogueras-Gonzalez GM, Kadia TM, Jabbour E, Bueso-Ramos CE, et al. Results of second salvage therapy in 673 adults with acute myelogenous leukemia treated at a single institution since 2000. Cancer. 2018;124(12):2534–40.

    CAS  PubMed  Google Scholar 

  45. DiNardo CD, Albitar M, Kadia TM, Naqvi K, Vaughan K, Cavazos A, et al. Venetoclax in combination with FLAG-IDA chemotherapy (FLAG-V-I) for fit, relapsed/refractory AML patients: interim results of a phase 1b/2 dose escalation and expansion study. Blood. 2018;132(Suppl 1):4048.

    Google Scholar 

  46. Wei AH, Chua CC, Tiong IS, Fong CY, Ting SB, Macraild S, et al. Molecular patterns of response and outcome in the chemotherapy and venetoclax in elderly AML trial (CAVEAT study). Blood. 2018;132(Suppl 1):333.

    Google Scholar 

  47. Kohl TM, Hellinger C, Ahmed F, Buske C, Hiddemann W, Bohlander SK, et al. BH3 mimetic ABT-737 neutralizes resistance to FLT3 inhibitor treatment mediated by FLT3-independent expression of BCL2 in primary AML blasts. Leukemia. 2007;21(8):1763–72.

    CAS  PubMed  Google Scholar 

  48. Ma J, Zhao S, Qiao X, Knight T, Edwards H, Polin L, et al. Inhibition of Bcl-2 synergistically enhances the antileukemic activity of midostaurin and gilteritinib in preclinical models of FLT3-mutated acute myeloid leukemia. Clin Cancer Res. 2019;25(22):6815–26.

    CAS  PubMed  PubMed Central  Google Scholar 

  49. Mali R, Lasater EA, Doyle K, Malla R, Boghaert E, Souers A, et al. Abstract B052: FLT3-ITD activation mediates resistance to the BCL-2 selective antagonist, venetoclax, in FLT3-ITD mutant AML models. Mol Cancer Therap. 2018;17(1 Suppl):B052.

    Google Scholar 

  50. Cathelin S, Sharon D, Subedi A, Cojocari D, Phillips DC, Leverson JD, et al. Combination of enasidenib and venetoclax shows superior anti-leukemic activity against IDH2 mutated AML in patient-derived xenograft models. Blood. 2018;132(Suppl 1):562.

    Google Scholar 

  51. Lachowiez CA, Borthakur G, Loghavi S, Zeng Z, Kadia TM, Masarova L, et al. Phase Ib/II study of the IDH1-mutant inhibitor ivosidenib with the BCL2 inhibitor venetoclax +/− azacitidine in IDH1-mutated hematologic malignancies. J Clin Oncol. 2020;38(15_Suppl):7500.

    Google Scholar 

  52. Karjalainen R, Pemovska T, Popa M, Liu M, Javarappa KK, Majumder MM, et al. JAK1/2 and BCL2 inhibitors synergize to counteract bone marrow stromal cell–induced protection of AML. Blood. 2017;130(6):789–802.

    CAS  PubMed  Google Scholar 

  53. Konopleva M, Milella M, Ruvolo P, Watts JC, Ricciardi MR, Korchin B, et al. MEK inhibition enhances ABT-737-induced leukemia cell apoptosis via prevention of ERK-activated MCL-1 induction and modulation of MCL-1/BIM complex. Leukemia. 2012;26(4):778–87.

    CAS  PubMed  Google Scholar 

  54. Mohamed R, Mandy Mayo A, Elisa H, Rebecca EP, Masey R, Maciej K, et al. Co-administration of the mTORC1/TORC2 inhibitor INK128 and the Bcl-2/Bcl-xL antagonist ABT-737 kills human myeloid leukemia cells through mcl-1 down-regulation and AKT inactivation. Haematologica. 2015;100(12):1553–63.

    Google Scholar 

  55. Lehmann C, Friess T, Birzele F, Kiialainen A, Dangl M. Superior anti-tumor activity of the MDM2 antagonist idasanutlin and the Bcl-2 inhibitor venetoclax in p53 wild-type acute myeloid leukemia models. J Hematol Oncol. 2016;9(1):50.

    PubMed  PubMed Central  Google Scholar 

  56. Tsao T, Shi Y, Kornblau S, Lu H, Konoplev S, Antony A, et al. Concomitant inhibition of DNA methyltransferase and BCL-2 protein function synergistically induce mitochondrial apoptosis in acute myelogenous leukemia cells. Ann Hematol. 2012;91(12):1861–70.

    CAS  PubMed  PubMed Central  Google Scholar 

  57. Daver N, Pollyea DA, Yee KWL, Fenaux P, Brandwein JM, Vey N, et al. Preliminary results from a phase Ib study evaluating BCL-2 inhibitor venetoclax in combination with MEK inhibitor cobimetinib or MDM2 inhibitor idasanutlin in patients with relapsed or refractory (R/R) AML. Blood. 2017;130(Suppl 1):813.

    Google Scholar 

  58. Marcucci G, Haferlach T, Döhner H. Molecular genetics of adult acute myeloid leukemia: prognostic and therapeutic implications. J Clin Oncol. 2011;29(5):475–86.

    CAS  PubMed  Google Scholar 

  59. Long J, Parkin B, Ouillette P, Bixby D, Shedden K, Erba H, et al. Multiple distinct molecular mechanisms influence sensitivity and resistance to MDM2 inhibitors in adult acute myelogenous leukemia. Blood. 2010;116(1):71–80.

    CAS  PubMed  PubMed Central  Google Scholar 

  60. Weisberg E, Halilovic E, Cooke VG, Nonami A, Ren T, Sanda T, et al. Inhibition of wild-type p53-expressing AML by the novel small molecule HDM2 inhibitor CGM097. Mol Cancer Ther. 2015;14(10):2249–59.

    CAS  PubMed  PubMed Central  Google Scholar 

  61. Saiki AY, Caenepeel S, Yu D, Lofgren JA, Osgood T, Robertson R, et al. MDM2 antagonists synergize broadly and robustly with compounds targeting fundamental oncogenic signaling pathways. Oncotarget. 2014;5(8):2030–43.

    PubMed  PubMed Central  Google Scholar 

  62. Tron AE, Belmonte MA, Adam A, Aquila BM, Boise LH, Chiarparin E, et al. Discovery of mcl-1-specific inhibitor AZD5991 and preclinical activity in multiple myeloma and acute myeloid leukemia. Nat Commun. 2018;9(1):1–14.

    Google Scholar 

  63. Kotschy A, Szlavik Z, Murray J, Davidson J, Maragno AL, Le Toumelin-Braizat G, et al. The MCL1 inhibitor S63845 is tolerable and effective in diverse cancer models. Nature. 2016;538(7626):477–82.

    PubMed  Google Scholar 

  64. Glaser SP, Lee EF, Trounson E, Bouillet P, Wei A, Fairlie WD, et al. Anti-apoptotic mcl-1 is essential for the development and sustained growth of acute myeloid leukemia. Genes Dev. 2012;26(2):120–5.

    CAS  PubMed  PubMed Central  Google Scholar 

  65. Zhang Z, Liu Y, Song T, Xue Z, Shen X, Liang F, et al. An antiapoptotic Bcl-2 family protein index predicts the response of leukaemic cells to the pan-Bcl-2 inhibitor S1. Br J Cancer. 2013;108(9):1870–8.

    CAS  PubMed  PubMed Central  Google Scholar 

  66. Michels J, Obrist F, Vitale I, Lissa D, Garcia P, Behnam-Motlagh P, et al. MCL-1 dependency of cisplatin-resistant cancer cells. Biochem Pharmacol. 2014;92(1):55–61.

    CAS  PubMed  Google Scholar 

  67. Wertz IE, Kusam S, Lam C, Okamoto T, Sandoval W, Anderson DJ, et al. Sensitivity to antitubulin chemotherapeutics is regulated by MCL1 and FBW7. Nature. 2011;471(7336):110–4.

    CAS  PubMed  Google Scholar 

  68. Williams MM, Lee L, Hicks DJ, Joly MM, Elion D, Rahman B, et al. Key survival factor, mcl-1, correlates with sensitivity to combined Bcl-2/Bcl-xL blockade. Mol Cancer Res. 2017;15(3):259–68.

    CAS  PubMed  Google Scholar 

  69. Thomas RL, Roberts DJ, Kubli DA, Lee Y, Quinsay MN, Owens JB, et al. Loss of MCL-1 leads to impaired autophagy and rapid development of heart failure. Genes Dev. 2013;27(12):1365–77.

    CAS  PubMed  PubMed Central  Google Scholar 

  70. Hikita H, Takehara T, Shimizu S, Kodama T, Li W, Miyagi T, et al. Mcl-1 and Bcl-xL cooperatively maintain integrity of hepatocytes in developing and adult murine liver. Hepatology. 2009;50(4):1217–26.

    CAS  PubMed  Google Scholar 

  71. Rasmussen ML, Kline LA, Park KP, Ortolano NA, Romero-Morales AI, Anthony CC, et al. A non-apoptotic function of MCL-1 in promoting Pluripotency and modulating mitochondrial dynamics in stem cells. Stem Cell Rep. 2018;10(3):684–92.

    Google Scholar 

  72. Hasan SMM, Sheen AD, Power AM, Langevin LM, Xiong J, Furlong M, et al. Mcl1 regulates the terminal mitosis of neural precursor cells in the mammalian brain through p27Kip1. Development. 2013;140(15):3118–27.

    CAS  PubMed  Google Scholar 

  73. Caenepeel S, Brown SP, Belmontes B, Moody G, Keegan KS, Chui D, et al. AMG 176, a selective MCL1 inhibitor, is effective in hematologic cancer models alone and in combination with established therapies. Cancer Discov. 2018;8(12):1582–97.

    CAS  PubMed  Google Scholar 

  74. Hird AW, Secrist JP, Adam A, Belmonte MA, Gangl E, Gibbons F, et al. Abstract DDT01–02: AZD5991: a potent and selective macrocyclic inhibitor of mcl-1 for treatment of hematologic cancers. Washington, DC: AACR; 2017.

    Google Scholar 

  75. Caenepeel SR, Belmontes B, Sun J, Coxon A, Moody G, Hughes PE. Preclinical evaluation of AMG 176, a novel, potent and selective mcl-1 inhibitor with robust anti-tumor activity in mcl-1 dependent cancer models. Washington, DC: AACR; 2017.

    Google Scholar 

  76. Hird AW, Tron AE. Recent advances in the development of mcl-1 inhibitors for cancer therapy. Pharmacol Ther. 2019;198:59–67.

    CAS  PubMed  Google Scholar 

  77. Amgen. Amgen Highlights New Data from Kyprolis (carfilzomib) and Oncology Pipeline at IMW 2019. 2019. https://www.amgen.com/media/news-releases/2019/09/amgen-highlights-new-data-from-kyprolis-carfilzomib-and-oncology-pipeline-at-imw-2019/.

  78. A study of venetoclax and AMG 176 in patients with relapsed/refractory hematologic malignancies. https://clinicaltrials.gov/ct2/show/NCT03797261.

  79. Phase I Study of S64315 administered intravenously in patients with acute myeloid leukaemia or myelodysplastic syndrome. https://clinicaltrials.gov/ct2/show/NCT02979366.

  80. Flynn J, Jones J, Johnson AJ, Andritsos L, Maddocks K, Jaglowski S, et al. Dinaciclib is a novel cyclin-dependent kinase inhibitor with significant clinical activity in relapsed and refractory chronic lymphocytic leukemia. Leukemia. 2015;29(7):1524–9.

    CAS  PubMed  PubMed Central  Google Scholar 

  81. Gojo I, Sadowska M, Walker A, Feldman EJ, Iyer SP, Baer MR, et al. Clinical and laboratory studies of the novel cyclin-dependent kinase inhibitor dinaciclib (SCH 727965) in acute leukemias. Cancer Chemother Pharmacol. 2013;72(4):897–908.

    CAS  PubMed  PubMed Central  Google Scholar 

  82. Kumar SK, LaPlant B, Chng WJ, Zonder J, Callander N, Fonseca R, et al. Dinaciclib, a novel CDK inhibitor, demonstrates encouraging single-agent activity in patients with relapsed multiple myeloma. Blood. 2015;125(3):443–8.

    CAS  PubMed  PubMed Central  Google Scholar 

  83. Han L, Zhang Q, Dail M, Shi C, Cavazos A, Ruvolo VR, et al. Concomitant targeting of BCL2 with venetoclax and MAPK signaling with cobimetinib in acute myeloid leukemia models. Haematologica. 2020;105(3):697–707.

    CAS  PubMed  PubMed Central  Google Scholar 

  84. Fiskus W, Cai T, DiNardo CD, Kornblau SM, Borthakur G, Kadia TM, et al. Superior efficacy of cotreatment with BET protein inhibitor and BCL2 or MCL1 inhibitor against AML blast progenitor cells. Blood Cancer J. 2019;9(2):4.

    PubMed  PubMed Central  Google Scholar 

  85. Cidado J, Boiko S, Proia T, Ferguson D, Criscione SW, San Martin M, et al. AZD4573 is a highly selective CDK9 inhibitor that suppresses MCL-1 and induces apoptosis in hematologic cancer cells. Clin Cancer Res. 2020;26(4):922–34.

    CAS  PubMed  Google Scholar 

  86. Xinyu L, Yongwei S, Katie H, Gerard M, Holly E, Tristan K, et al. The HDAC and PI3K dual inhibitor CUDC-907 synergistically enhances the antileukemic activity of venetoclax in preclinical models of acute myeloid leukemia. Haematologica. 2021;106(5):1262–77.

    Google Scholar 

  87. Pan R, Ruvolo V, Mu H, Leverson JD, Nichols G, Reed JC, et al. Synthetic lethality of combined Bcl-2 inhibition and p53 activation in AML: mechanisms and superior antileukemic efficacy. Cancer Cell. 2017;32(6):748–60.e6.

    CAS  PubMed  PubMed Central  Google Scholar 

  88. Rahmani M, Nkwocha J, Hawkins E, Pei X, Parker RE, Kmieciak M, et al. Cotargeting BCL-2 and PI3K induces BAX-dependent mitochondrial apoptosis in AML cells. Cancer Res. 2018;78(11):3075–86.

    CAS  PubMed  PubMed Central  Google Scholar 

  89. Luedtke DA, Su Y, Liu S, Edwards H, Wang Y, Lin H, et al. Inhibition of XPO1 enhances cell death induced by ABT-199 in acute myeloid leukaemia via mcl-1. J Cell Mol Med. 2018;22(12):6099–111.

    CAS  PubMed  PubMed Central  Google Scholar 

  90. Lee JS, Roberts A, Juarez D, Vo TT, Bhatt S, Herzog LO, et al. Statins enhance efficacy of venetoclax in blood cancers. Sci Transl Med. 2018;10(445):eaaq1240.

    PubMed  PubMed Central  Google Scholar 

  91. Eide CA, Kurtz SE, Kaempf A, Long N, Agarwal A, Tognon CE, et al. Simultaneous kinase inhibition with ibrutinib and BCL2 inhibition with venetoclax offers a therapeutic strategy for acute myeloid leukemia. Leukemia. 2020;34(9):2342–53.

    CAS  PubMed  PubMed Central  Google Scholar 

  92. Elgamal OA, Mehmood A, Jeon JY, Carmichael B, Lehman A, Orwick SJ, et al. Preclinical efficacy for a novel tyrosine kinase inhibitor, ArQule 531 against acute myeloid leukemia. J Hematol Oncol. 2020;13(1):8.

    CAS  PubMed  PubMed Central  Google Scholar 

  93. Sharon D, Cathelin S, Mirali S, Di Trani JM, Yanofsky DJ, Keon KA, et al. Inhibition of mitochondrial translation overcomes venetoclax resistance in AML through activation of the integrated stress response. Sci Transl Med. 2019;11(516):eaax2863.

    CAS  PubMed  Google Scholar 

  94. Pollyea DA, Stevens BM, Jones CL, Winters A, Pei S, Minhajuddin M, et al. Venetoclax with azacitidine disrupts energy metabolism and targets leukemia stem cells in patients with acute myeloid leukemia. Nat Med. 2018;24(12):1859–66.

    CAS  PubMed  PubMed Central  Google Scholar 

  95. Nechiporuk T, Kurtz SE, Nikolova O, Liu T, Jones CL, D’Alessandro A, et al. The TP53 apoptotic network is a primary mediator of resistance to BCL2 inhibition in AML cells. Cancer Discov. 2019;9(7):910–25.

    CAS  PubMed  PubMed Central  Google Scholar 

  96. Chen X, Glytsou C, Zhou H, Narang S, Reyna DE, Lopez A, et al. Targeting mitochondrial structure sensitizes acute myeloid leukemia to venetoclax treatment. Cancer Discov. 2019;9(7):890–909.

    CAS  PubMed  PubMed Central  Google Scholar 

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Authors and Affiliations

  1. Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada

    Kenny Tang & Steven M. Chan

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  1. Kenny Tang
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  2. Steven M. Chan
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Correspondence to Steven M. Chan .

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  1. Department of Medicine, Queen Mary Hospital, Hongkong, Hong Kong

    Harinder Gill

  2. Department of Medicine, Queen Mary Hospital, Hongkong, Hong Kong

    Yok-Lam Kwong

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Tang, K., Chan, S.M. (2023). The Role of BCL-2/MCL-1 Targeting in Acute Myeloid Leukemia. In: Gill, H., Kwong, YL. (eds) Pathogenesis and Treatment of Leukemia. Springer, Singapore. https://doi.org/10.1007/978-981-99-3810-0_10

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  • DOI: https://doi.org/10.1007/978-981-99-3810-0_10

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