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Drugs

, Volume 79, Issue 12, pp 1287–1304 | Cite as

Targeting BCL2 in Chronic Lymphocytic Leukemia and Other Hematologic Malignancies

  • Fevzi F. Yalniz
  • William G. WierdaEmail author
Leading Article

Abstract

Apoptosis, the process of programmed cell death, occurs normally during development and aging. Members of the B-cell lymphoma 2 (BCL2) family of proteins are central regulators of apoptosis, and resistance to apoptosis is one of the hallmarks of cancer. Targeting the apoptotic pathway via BCL2 inhibitors has been considered a promising treatment strategy in the past decade. Initial efforts with small molecule BH3 mimetics such as ABT-737 and ABT-263 (navitoclax) pioneered the development of the first-in-class Food and Drug Administration (FDA)-approved oral BCL2 inhibitor, venetoclax. Venetoclax was approved for the treatment of chronic lymphocytic leukemia and acute myeloid leukemia, and is now being studied in a number of hematologic malignancies. Several other inhibitors targeting different BCL2 family members are now in early stages of development.

Notes

Compliance with Ethical Standards

Funding

No external funding was used in the preparation of this article.

Conflict of interest

Dr. William G. Wierda and Dr. Fevzi F. Yalniz declare that they have no conflicts of interest that might be relevant to the contents of this article.

References

  1. 1.
    Kerr JF, Wyllie AH, Currie AR. Apoptosis: a basic biological phenomenon with wide-ranging implications in tissue kinetics. Br J Cancer. 1972;26(4):239–57.PubMedPubMedCentralGoogle Scholar
  2. 2.
    Chen M, Wang J. Initiator caspases in apoptosis signaling pathways. Apoptosis. 2002;7(4):313–9.PubMedGoogle Scholar
  3. 3.
    Adams JM, Cory S. The BCL-2 arbiters of apoptosis and their growing role as cancer targets. Cell Death Differ. 2018;25(1):27–36.Google Scholar
  4. 4.
    Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011;144(5):646–74.Google Scholar
  5. 5.
    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.Google Scholar
  6. 6.
    Yip KW, Reed JC. Bcl-2 family proteins and cancer. Oncogene. 2008;27(50):6398–406.PubMedGoogle Scholar
  7. 7.
    Czabotar PE, Lessene G. Bcl-2 family proteins as therapeutic targets. Curr Pharm Des. 2010;16(28):3132–48.PubMedGoogle Scholar
  8. 8.
    Leber B, Lin J, Andrews DW. Embedded together: the life and death consequences of interaction of the Bcl-2 family with membranes. Apoptosis. 2007;12(5):897–911.PubMedPubMedCentralGoogle Scholar
  9. 9.
    Tsujimoto Y, Cossman J, Jaffe E, Croce CM. Involvement of the bcl-2 gene in human follicular lymphoma. Science. 1985;228(4706):1440–3.PubMedPubMedCentralGoogle Scholar
  10. 10.
    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.PubMedGoogle Scholar
  11. 11.
    Huang J, Fairbrother W, Reed JC. Therapeutic targeting of Bcl-2 family for treatment of B-cell malignancies. Expert Rev Hematol. 2015;8(3):283–97.PubMedGoogle Scholar
  12. 12.
    Chresta CM, Arriola EL, Hickman JA. Apoptosis and cancer chemotherapy. Behring Inst Mitt. 1996;97:232–40.Google Scholar
  13. 13.
    Behbahani TE, Thierse C, Baumann C, et al. Tyrosine kinase expression profile in clear cell renal cell carcinoma. World J Urol. 2012;30(4):559–65.Google Scholar
  14. 14.
    Zhang GJ, Kimijima I, Tsuchiya A, Abe R. The role of bcl-2 expression in breast carcinomas (Review). Oncol Rep. 1998;5(5):1211–6.PubMedGoogle Scholar
  15. 15.
    Grimm KE, O’Malley DP. Aggressive B cell lymphomas in the 2017 revised WHO classification of tumors of hematopoietic and lymphoid tissues. Ann Diagn Pathol. 2018;38:6–10.PubMedGoogle Scholar
  16. 16.
    Iqbal J, Sanger WG, Horsman DE, et al. BCL2 translocation defines a unique tumor subset within the germinal center B-cell-like diffuse large B-cell lymphoma. Am J Pathol. 2004;165(1):159–66.PubMedPubMedCentralGoogle Scholar
  17. 17.
    Huang JZ, Sanger WG, Greiner TC, et al. The t(14;18) defines a unique subset of diffuse large B-cell lymphoma with a germinal center B-cell gene expression profile. Blood. 2002;99(7):2285–90.PubMedGoogle Scholar
  18. 18.
    Davis RE, Brown KD, Siebenlist U, Staudt LM. Constitutive nuclear factor kappaB activity is required for survival of activated B cell-like diffuse large B cell lymphoma cells. J Exp Med. 2001;194(12):1861–74.PubMedPubMedCentralGoogle Scholar
  19. 19.
    Piris MA, Pezzella F, Martinez-Montero JC, et al. p53 and bcl-2 expression in high-grade B-cell lymphomas: correlation with survival time. Br J Cancer. 1994;69(2):337–41.PubMedPubMedCentralGoogle Scholar
  20. 20.
    Tang SC, Visser L, Hepperle B, Hanson J, Poppema S. Clinical significance of bcl-2-MBR gene rearrangement and protein expression in diffuse large-cell non-Hodgkin’s lymphoma: an analysis of 83 cases. J Clin Oncol. 1994;12(1):149–54.PubMedGoogle Scholar
  21. 21.
    Martinka M, Comeau T, Foyle A, Anderson D, Greer W. Prognostic significance of t(14;18) and bcl-2 gene expression in follicular small cleaved cell lymphoma and diffuse large cell lymphoma. Clin Investig Med. 1997;20(6):364–70.Google Scholar
  22. 22.
    Barrans SL, Carter I, Owen RG, et al. Germinal center phenotype and bcl-2 expression combined with the International Prognostic Index improves patient risk stratification in diffuse large B-cell lymphoma. Blood. 2002;99(4):1136–43.PubMedGoogle Scholar
  23. 23.
    Snuderl M, Kolman OK, Chen YB, et al. B-cell lymphomas with concurrent IGH-BCL2 and MYC rearrangements are aggressive neoplasms with clinical and pathologic features distinct from Burkitt lymphoma and diffuse large B-cell lymphoma. Am J Surg Pathol. 2010;34(3):327–40.PubMedPubMedCentralGoogle Scholar
  24. 24.
    Swerdlow SH, Williams ME. From centrocytic to mantle cell lymphoma: a clinicopathologic and molecular review of 3 decades. Hum Pathol. 2002;33(1):7–20.PubMedGoogle Scholar
  25. 25.
    Rosenwald A, Wright G, Wiestner A, et al. The proliferation gene expression signature is a quantitative integrator of oncogenic events that predicts survival in mantle cell lymphoma. Cancer Cell. 2003;3(2):185–97.PubMedGoogle Scholar
  26. 26.
    Bodrug SE, Warner BJ, Bath ML, Lindeman GJ, Harris AW, Adams JM. Cyclin D1 transgene impedes lymphocyte maturation and collaborates in lymphomagenesis with the myc gene. EMBO J. 1994;13(9):2124–30.PubMedPubMedCentralGoogle Scholar
  27. 27.
    Lovec H, Grzeschiczek A, Kowalski MB, Moroy T. Cyclin D1/bcl-1 cooperates with myc genes in the generation of B-cell lymphoma in transgenic mice. EMBO J. 1994;13(15):3487–95.PubMedPubMedCentralGoogle Scholar
  28. 28.
    Mestre-Escorihuela C, Rubio-Moscardo F, Richter JA, et al. Homozygous deletions localize novel tumor suppressor genes in B-cell lymphomas. Blood. 2007;109(1):271–80.PubMedGoogle Scholar
  29. 29.
    Tagawa H, Karnan S, Suzuki R, et al. Genome-wide array-based CGH for mantle cell lymphoma: identification of homozygous deletions of the proapoptotic gene BIM. Oncogene. 2005;24(8):1348–58.PubMedGoogle Scholar
  30. 30.
    Katz SG, Labelle JL, Meng H, et al. Mantle cell lymphoma in cyclin D1 transgenic mice with Bim-deficient B cells. Blood. 2014;123(6):884–93.PubMedPubMedCentralGoogle Scholar
  31. 31.
    Amin HM, McDonnell TJ, Medeiros LJ, et al. Characterization of 4 mantle cell lymphoma cell lines. Arch Pathol Lab Med. 2003;127(4):424–31.PubMedPubMedCentralGoogle Scholar
  32. 32.
    Perez-Galan P, Roue G, Villamor N, Campo E, Colomer D. The BH3-mimetic GX15-070 synergizes with bortezomib in mantle cell lymphoma by enhancing Noxa-mediated activation of Bak. Blood. 2007;109(10):4441–9.PubMedGoogle Scholar
  33. 33.
    Rudolph C, Steinemann D, Von Neuhoff N, et al. Molecular cytogenetic characterization of the mantle cell lymphoma cell line GRANTA-519. Cancer Genet Cytogenet. 2004;153(2):144–50.PubMedPubMedCentralGoogle Scholar
  34. 34.
    Touzeau C, Dousset C, Bodet L, et al. ABT-737 induces apoptosis in mantle cell lymphoma cells with a Bcl-2high/Mcl-1low profile and synergizes with other antineoplastic agents. Clin Cancer Res. 2011;17(18):5973–81.PubMedGoogle Scholar
  35. 35.
    Khoury JD, Medeiros LJ, Rassidakis GZ, McDonnell TJ, Abruzzo LV, Lai R. Expression of Mcl-1 in mantle cell lymphoma is associated with high-grade morphology, a high proliferative state, and p53 overexpression. J Pathol. 2003;199(1):90–7.PubMedGoogle Scholar
  36. 36.
    Dohner H, Stilgenbauer S, Benner A, et al. Genomic aberrations and survival in chronic lymphocytic leukemia. N Engl J Med. 2000;343(26):1910–6.PubMedGoogle Scholar
  37. 37.
    Edelmann J, Holzmann K, Miller F, et al. High-resolution genomic profiling of chronic lymphocytic leukemia reveals new recurrent genomic alterations. Blood. 2012;120(24):4783–94.PubMedGoogle Scholar
  38. 38.
    Dong JT, Boyd JC, Frierson HF Jr. Loss of heterozygosity at 13q14 and 13q21 in high grade, high stage prostate cancer. Prostate. 2001;49(3):166–71.Google Scholar
  39. 39.
    Bullrich F, Fujii H, Calin G, et al. Characterization of the 13q14 tumor suppressor locus in CLL: identification of ALT1, an alternative splice variant of the LEU2 gene. Cancer Res. 2001;61(18):6640–8.PubMedGoogle Scholar
  40. 40.
    Migliazza A, Bosch F, Komatsu H, et al. Nucleotide sequence, transcription map, and mutation analysis of the 13q14 chromosomal region deleted in B-cell chronic lymphocytic leukemia. Blood. 2001;97(7):2098–104.PubMedGoogle Scholar
  41. 41.
    Mabuchi H, Fujii H, Calin G, et al. Cloning and characterization of CLLD6, CLLD7, and CLLD8, novel candidate genes for leukemogenesis at chromosome 13q14, a region commonly deleted in B-cell chronic lymphocytic leukemia. Cancer Res. 2001;61(7):2870–7.PubMedGoogle Scholar
  42. 42.
    Calin GA, Dumitru CD, Shimizu M, et al. Frequent deletions and down-regulation of micro- RNA genes miR15 and miR16 at 13q14 in chronic lymphocytic leukemia. Proc Natl Acad Sci USA. 2002;99(24):15524–9.PubMedGoogle Scholar
  43. 43.
    Cimmino A, Calin GA, Fabbri M, et al. miR-15 and miR-16 induce apoptosis by targeting BCL2. Proc Natl Acad Sci USA. 2005;102(39):13944–9.Google Scholar
  44. 44.
    Scarfo L, Ghia P. Reprogramming cell death: BCL2 family inhibition in hematological malignancies. Immunol Lett. 2013;155(1–2):36–9.PubMedGoogle Scholar
  45. 45.
    Bodet L, Gomez-Bougie P, Touzeau C, et al. ABT-737 is highly effective against molecular subgroups of multiple myeloma. Blood. 2011;118(14):3901–10.PubMedGoogle Scholar
  46. 46.
    Touzeau C, Maciag P, Amiot M, Moreau P. Targeting Bcl-2 for the treatment of multiple myeloma. Leukemia. 2018;32(9):1899–907.PubMedGoogle Scholar
  47. 47.
    Bodet L, Menoret E, Descamps G, et al. BH3-only protein Bik is involved in both apoptosis induction and sensitivity to oxidative stress in multiple myeloma. Br J Cancer. 2010;103(12):1808–14.PubMedPubMedCentralGoogle Scholar
  48. 48.
    Kumar S, Kaufman JL, Gasparetto C, et al. Efficacy of venetoclax as targeted therapy for relapsed/refractory t(11;14) multiple myeloma. Blood. 2017;130(22):2401–9.PubMedGoogle Scholar
  49. 49.
    Park JR, Bernstein ID, Hockenbery DM. Primitive human hematopoietic precursors express Bcl-x but not Bcl-2. Blood. 1995;86(3):868–76.PubMedGoogle Scholar
  50. 50.
    Andreeff M, Jiang S, Zhang X, et al. Expression of Bcl-2-related genes in normal and AML progenitors: changes induced by chemotherapy and retinoic acid. Leukemia. 1999;13(11):1881–92.PubMedGoogle Scholar
  51. 51.
    Venditti A, Del Poeta G, Maurillo L, et al. Combined analysis of bcl-2 and MDR1 proteins in 256 cases of acute myeloid leukemia. Haematologica. 2004;89(8):934–9.PubMedGoogle Scholar
  52. 52.
    Wuchter C, Karawajew L, Ruppert V, et al. Clinical significance of CD95, Bcl-2 and Bax expression and CD95 function in adult de novo acute myeloid leukemia in context of P-glycoprotein function, maturation stage, and cytogenetics. Leukemia. 1999;13(12):1943–53.PubMedGoogle Scholar
  53. 53.
    Kornblau SM, Thall PF, Estrov Z, et al. The prognostic impact of BCL2 protein expression in acute myelogenous leukemia varies with cytogenetics. Clin Cancer Res. 1999;5(7):1758–66.PubMedGoogle Scholar
  54. 54.
    Del Poeta G, Venditti A, Del Principe MI, et al. Amount of spontaneous apoptosis detected by Bax/Bcl-2 ratio predicts outcome in acute myeloid leukemia (AML). Blood. 2003;101(6):2125–31.PubMedGoogle Scholar
  55. 55.
    Ong YL, McMullin MF, Bailie KE, Lappin TR, Jones FG, Irvine AE. High bax expression is a good prognostic indicator in acute myeloid leukaemia. Br J Haematol. 2000;111(1):182–9.PubMedGoogle Scholar
  56. 56.
    Kohler T, Schill C, Deininger MW, et al. High Bad and Bax mRNA expression correlate with negative outcome in acute myeloid leukemia (AML). Leukemia. 2002;16(1):22–9.PubMedGoogle Scholar
  57. 57.
    Kulsoom B, Shamsi TS, Afsar NA, Memon Z, Ahmed N, Hasnain SN. Bax, Bcl-2, and Bax/Bcl-2 as prognostic markers in acute myeloid leukemia: are we ready for Bcl-2-directed therapy? Cancer Manag Res. 2018;10:403–16.PubMedCentralGoogle Scholar
  58. 58.
    Doussis IA, Pezzella F, Lane DP, Gatter KC, Mason DY. An immunocytochemical study of p53 and bcl-2 protein expression in Hodgkin’s disease. Am J Clin Pathol. 1993;99(6):663–7.PubMedGoogle Scholar
  59. 59.
    Hell K, Lorenzen J, Fischer R, Hansmann ML. Hodgkin cells accumulate mRNA for bcl-2. Lab Investig. 1995;73(4):492–6.PubMedGoogle Scholar
  60. 60.
    Rassidakis GZ, Medeiros LJ, Vassilakopoulos TP, et al. BCL-2 expression in Hodgkin and Reed-Sternberg cells of classical Hodgkin disease predicts a poorer prognosis in patients treated with ABVD or equivalent regimens. Blood. 2002;100(12):3935–41.PubMedGoogle Scholar
  61. 61.
    Jaiswal S, Traver D, Miyamoto T, Akashi K, Lagasse E, Weissman IL. Expression of BCR/ABL and BCL-2 in myeloid progenitors leads to myeloid leukemias. Proc Natl Acad Sci USA. 2003;100(17):10002–7.PubMedGoogle Scholar
  62. 62.
    Aichberger KJ, Mayerhofer M, Krauth MT, et al. Identification of mcl-1 as a BCR/ABL-dependent target in chronic myeloid leukemia (CML): evidence for cooperative antileukemic effects of imatinib and mcl-1 antisense oligonucleotides. Blood. 2005;105(8):3303–11.PubMedGoogle Scholar
  63. 63.
    Horita M, Andreu EJ, Benito A, et al. Blockade of the Bcr-Abl kinase activity induces apoptosis of chronic myelogenous leukemia cells by suppressing signal transducer and activator of transcription 5-dependent expression of Bcl-xL. J Exp Med. 2000;191(6):977–84.PubMedPubMedCentralGoogle Scholar
  64. 64.
    Gala JL, Vermylen C, Cornu G, et al. High expression of bcl-2 is the rule in acute lymphoblastic leukemia, except in Burkitt subtype at presentation, and is not correlated with the prognosis. Ann Hematol. 1994;69(1):17–24.PubMedGoogle Scholar
  65. 65.
    Del Gaizo Moore V, Schlis KD, Sallan SE, Armstrong SA, Letai A. BCL-2 dependence and ABT-737 sensitivity in acute lymphoblastic leukemia. Blood. 2008;111(4):2300–9.Google Scholar
  66. 66.
    Sapienza MR, Fuligni F, Agostinelli C, et al. Molecular profiling of blastic plasmacytoid dendritic cell neoplasm reveals a unique pattern and suggests selective sensitivity to NF-kB pathway inhibition. Leukemia. 2014;28(8):1606–16.PubMedPubMedCentralGoogle Scholar
  67. 67.
    Montero J, Stephansky J, Cai T, et al. Blastic plasmacytoid dendritic cell neoplasm is dependent on BCL2 and sensitive to venetoclax. Cancer Discov. 2017;7(2):156–64.PubMedGoogle Scholar
  68. 68.
    Schlagbauer-Wadl H, Klosner G, Heere-Ress E, et al. Bcl-2 antisense oligonucleotides (G3139) inhibit Merkel cell carcinoma growth in SCID mice. J Investig Dermatol. 2000;114(4):725–30.PubMedGoogle Scholar
  69. 69.
    Pepper C, Hooper K, Thomas A, Hoy T, Bentley P. Bcl-2 antisense oligonucleotides enhance the cytotoxicity of chlorambucil in B-cell chronic lymphocytic leukaemia cells. Leuk Lymphoma. 2001;42(3):491–8.PubMedGoogle Scholar
  70. 70.
    Auer RL, Corbo M, Fegan CD, et al. Bcl-2 antisense (Genasense) induces apoptosis and potentiates activity of both cytotoxic chemotherapy and rituximab in primary CLL cells. Blood. 2001;98:808a (abstr 3358).Google Scholar
  71. 71.
    O’Brien SM, Cunningham CC, Golenkov AK, Turkina AG, Novick SC, Rai KR. Phase I to II multicenter study of oblimersen sodium, a Bcl-2 antisense oligonucleotide, in patients with advanced chronic lymphocytic leukemia. J Clin Oncol. 2005;23(30):7697–702.PubMedGoogle Scholar
  72. 72.
    O’Brien S, Moore JO, Boyd TE, et al. 5-year survival in patients with relapsed or refractory chronic lymphocytic leukemia in a randomized, phase III trial of fludarabine plus cyclophosphamide with or without oblimersen. J Clin Oncol. 2009;27(31):5208–12.PubMedPubMedCentralGoogle Scholar
  73. 73.
    Waters JS, Webb A, Cunningham D, et al. Phase I clinical and pharmacokinetic study of bcl-2 antisense oligonucleotide therapy in patients with non-Hodgkin’s lymphoma. J Clin Oncol. 2000;18(9):1812–23.PubMedGoogle Scholar
  74. 74.
    Pro B, Leber B, Smith M, et al. Phase II multicenter study of oblimersen sodium, a Bcl-2 antisense oligonucleotide, in combination with rituximab in patients with recurrent B-cell non-Hodgkin lymphoma. Br J Haematol. 2008;143(3):355–60.PubMedGoogle Scholar
  75. 75.
    Kitada S, Leone M, Sareth S, Zhai D, Reed JC, Pellecchia M. Discovery, characterization, and structure-activity relationships studies of proapoptotic polyphenols targeting B-cell lymphocyte/leukemia-2 proteins. J Med Chem. 2003;46(20):4259–64.PubMedGoogle Scholar
  76. 76.
    Zhai D, Jin C, Satterthwait AC, Reed JC. Comparison of chemical inhibitors of antiapoptotic Bcl-2-family proteins. Cell Death Differ. 2006;13(8):1419–21.PubMedGoogle Scholar
  77. 77.
    Oliver CL, Bauer JA, Wolter KG, et al. In vitro effects of the BH3 mimetic, (–)-gossypol, on head and neck squamous cell carcinoma cells. Clin Cancer Res. 2004;10(22):7757–63.PubMedGoogle Scholar
  78. 78.
    Liu S, Kulp SK, Sugimoto Y, et al. The (–)-enantiomer of gossypol possesses higher anticancer potency than racemic gossypol in human breast cancer. Anticancer Res. 2002;22(1A):33–8.PubMedGoogle Scholar
  79. 79.
    James DF, Castro JE, Loria O, Prada CE, Aguillon RA, Kipps TJ. AT-101, a small molecule Bcl-2 antagonist, in treatment naive CLL patients (pts) with high risk features; Preliminary results from an ongoing phase I trial. J Clin Oncol (ASCO Meeting Abstracts). 2006;24:6605.Google Scholar
  80. 80.
    Castro JE, Olivier LJ, Robier AA, Danelle J, Carlos SJ, Bi-Ying Y, Thomas KJ. A phase II, open label study of AT-101 in combination with rituximab in patients with relapsed or refractory chronic lymphocytic leukemia. Blood (ASH Annual Meeting Abstracts). 2006;108:2838.Google Scholar
  81. 81.
    Kingsley E, Richards D, Garbo L, Gersh R, Robbins G, Leopold L, Brill J, Di Bella N. An open-label, multicenter, phase II study of AT-101 in combination with rituximab® in patients with untreated, grade 1-2, follicular non-Hodgkin’s lymphoma (FL). J Clin Oncol. 2009;27:8582.Google Scholar
  82. 82.
    Konopleva M, Watt J, Contractor R, 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.PubMedPubMedCentralGoogle Scholar
  83. 83.
    Bonapace L, Bornhauser BC, Schmitz M, et al. Induction of autophagy-dependent necroptosis is required for childhood acute lymphoblastic leukemia cells to overcome glucocorticoid resistance. J Clin Investig. 2010;120(4):1310–23.PubMedGoogle Scholar
  84. 84.
    Herishanu Y, Gibellini F, Njuguna N, et al. Activation of CD44, a receptor for extracellular matrix components, protects chronic lymphocytic leukemia cells from spontaneous and drug induced apoptosis through MCL-1. Leuk Lymphoma. 2011;52(9):1758–69.PubMedPubMedCentralGoogle Scholar
  85. 85.
    Campas C, Cosialls AM, Barragan M, et al. Bcl-2 inhibitors induce apoptosis in chronic lymphocytic leukemia cells. Exp Hematol. 2006;34(12):1663–9.PubMedGoogle Scholar
  86. 86.
    Brem EA, Thudium K, Khubchandani S, et al. Distinct cellular and therapeutic effects of obatoclax in rituximab-sensitive and -resistant lymphomas. Br J Haematol. 2011;153(5):599–611.PubMedPubMedCentralGoogle Scholar
  87. 87.
    Trudel S, Li ZH, Rauw J, Tiedemann RE, Wen XY, Stewart AK. Preclinical studies of the pan-Bcl inhibitor obatoclax (GX015-070) in multiple myeloma. Blood. 2007;109(12):5430–8.PubMedGoogle Scholar
  88. 88.
    O’Brien SM, Claxton DF, Crump M, et al. Phase I study of obatoclax mesylate (GX15-070), a small molecule pan-Bcl-2 family antagonist, in patients with advanced chronic lymphocytic leukemia. Blood. 2009;113(2):299–305.PubMedPubMedCentralGoogle Scholar
  89. 89.
    Schimmer AD, O’Brien S, Kantarjian H, 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.PubMedGoogle Scholar
  90. 90.
    Goy AG, Ford P, Feldman T, et al. A phase I trial of the pan Bcl-2 family inhibitor obatoclax mesylate (GX15-070) in combination with bortezomib in patients with relapsed/refractory mantle cell lymphoma. Blood (ASH Annual Meeting Abstracts). 2007;110(11):Abstract 2569.Google Scholar
  91. 91.
    Brown JR, Tesar B, Yu L, et al. Obatoclax in combination with fludarabine and rituximab is well-tolerated and shows promising clinical activity in relapsed chronic lymphocytic leukemia. Leuk Lymphoma. 2015;56(12):3336–42.PubMedGoogle Scholar
  92. 92.
    Oltersdorf T, Elmore SW, Shoemaker AR, et al. An inhibitor of Bcl-2 family proteins induces regression of solid tumours. Nature. 2005;435(7042):677–81.PubMedPubMedCentralGoogle Scholar
  93. 93.
    Bruncko M, Oost TK, Belli BA, et al. Studies leading to potent, dual inhibitors of Bcl-2 and Bcl-xL. J Med Chem. 2007;50(4):641–62.PubMedGoogle Scholar
  94. 94.
    Tse C, Shoemaker AR, Adickes J, et al. ABT-263: a potent and orally bioavailable Bcl-2 family inhibitor. Cancer Res. 2008;68(9):3421–8.PubMedGoogle Scholar
  95. 95.
    Ackler S, Xiao Y, Mitten MJ, et al. ABT-263 and rapamycin act cooperatively to kill lymphoma cells in vitro and in vivo. Mol Cancer Ther. 2008;7(10):3265–74.PubMedGoogle Scholar
  96. 96.
    Wilson WH, O’Connor OA, Czuczman MS, et al. Navitoclax, a targeted high-affinity inhibitor of BCL-2, in lymphoid malignancies: a phase 1 dose-escalation study of safety, pharmacokinetics, pharmacodynamics, and antitumour activity. Lancet Oncol. 2010;11(12):1149–59.PubMedPubMedCentralGoogle Scholar
  97. 97.
    Roberts AW, Seymour JF, Brown JR, 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.Google Scholar
  98. 98.
    Kipps TJ, Eradat H, Grosicki S, et al. A phase 2 study of the BH3 mimetic BCL2 inhibitor navitoclax (ABT-263) with or without rituximab, in previously untreated B-cell chronic lymphocytic leukemia. Leuk Lymphoma. 2015;56(10):2826–33.PubMedPubMedCentralGoogle Scholar
  99. 99.
    Souers AJ, Leverson JD, Boghaert ER, et al. ABT-199, a potent and selective BCL-2 inhibitor, achieves antitumor activity while sparing platelets. Nat Med. 2013;19(2):202–8.Google Scholar
  100. 100.
    Roberts AW, Davids MS, Pagel JM, et al. Targeting BCL2 with Venetoclax in Relapsed Chronic Lymphocytic Leukemia. N Engl J Med. 2016;374(4):311–22.Google Scholar
  101. 101.
    Davids MS, Roberts AW, Seymour JF, et al. Safety, efficacy and immune effects of venetoclax 400 mg daily in patients with relapsed chronic lymphocytic leukemia (CLL). ASCO Meeting Abstracts. 2016;34(15 suppl):7527.Google Scholar
  102. 102.
    Stilgenbauer S, Eichhorst B, Schetelig J, et al. Venetoclax in relapsed or refractory chronic lymphocytic leukaemia with 17p deletion: a multicentre, open-label, phase 2 study. Lancet Oncol. 2016;17(6):768–78.PubMedGoogle Scholar
  103. 103.
    Jones JA, Wierda WG, Choi MY, et al. Venetoclax activity in CLL patients who have relapsed after or are refractory to ibrutinib or idelalisib. ASCO Meeting Abstracts. 2016;34(15 suppl):7519.Google Scholar
  104. 104.
    Coutre S, Choi M, Furman RR, et al. Venetoclax for patients with chronic lymphocytic leukemia who progressed during or after idelalisib therapy. Blood. 2018;131(15):1704–11.PubMedPubMedCentralGoogle Scholar
  105. 105.
    Davids MS, Hallek M, Wierda W, et al. Comprehensive safety analysis of venetoclax monotherapy for patients with relapsed/refractory chronic lymphocytic leukemia. Clin Cancer Res. 2018;24(18):4371–9.PubMedGoogle Scholar
  106. 106.
    Seymour JF, Ma S, Brander DM, et al. Venetoclax plus rituximab in relapsed or refractory chronic lymphocytic leukaemia: a phase 1b study. Lancet Oncol. 2017;18(2):230–40.PubMedPubMedCentralGoogle Scholar
  107. 107.
    Flinn IW, Gribben JG, Dyer MJS, et al. Phase 1b study of venetoclax-obinutuzumab in previously untreated and relapsed/refractory chronic lymphocytic leukemia. Blood. 2019;133:2765–75.PubMedPubMedCentralGoogle Scholar
  108. 108.
    Fischer K, Al-Sawaf O, Fink A, Dixon M, Bahlo J, Warburton S, Kipps TJ, Weinkove R, Robinson S, Dreyling MH, Opat S, Owen CJ, López J, Humphrey K, Humerickhouse RA, Tausch E, Eichhorst B, Wendtner C, Langerak AW, van Dongen JJ, Ritgen M, Boettcher S, Stilgenbauer S, Goede V, Mobasher M, Hallek M. Safety and efficacy of venetoclax and obinutuzumab in patients with previously untreated chronic lymphocytic leukemia (CLL) and coexisting medical conditions: final results of the run-in phase of the randomized CLL14 trial (BO25323). Blood. 2016;128(22):2054. http://www.bloodjournal.org/content/128/22/2054. Accessed 23 March 2019.Google Scholar
  109. 109.
    Seymour JF, Kipps TJ, Eichhorst B, et al. Venetoclax-rituximab in relapsed or refractory chronic lymphocytic leukemia. N Engl J Med. 2018;378(12):1107–20.PubMedGoogle Scholar
  110. 110.
    Kater AP, Seymour JF, Hillmen P, et al. Fixed duration of venetoclax-rituximab in relapsed/refractory chronic lymphocytic leukemia eradicates minimal residual disease and prolongs survival: post-treatment follow-up of the MURANO phase III study. J Clin Oncol. 2019;37(4):269–77.PubMedGoogle Scholar
  111. 111.
    Fischer K, Al-Sawaf O, Fink AM, et al. Venetoclax and obinutuzumab in chronic lymphocytic leukemia. Blood. 2017;129(19):2702–5.PubMedPubMedCentralGoogle Scholar
  112. 112.
    Cervantes-Gomez F, Lamothe B, Woyach JA, et al. Pharmacological and protein profiling suggests venetoclax (ABT-199) as optimal partner with ibrutinib in chronic lymphocytic leukemia. Clin Cancer Res. 2015;21(16):3705–15.PubMedPubMedCentralGoogle Scholar
  113. 113.
    Jain N, Keating MJ, Thompson PA, et al. Combined ibrutinib and venetoclax in patients with treatment naive high risk CLL. ASH Annual Meeting Abstracts. 2018;Abstract 186.Google Scholar
  114. 114.
    Hillmen P, Rawstron A, Brock K, et al. Ibrutinib plus venetoclax in relapsed/refractory CLL: results of the bloodwise TAP Clarity study. ASH Annual Meeting Abstracts. 2018;Abstract 182.Google Scholar
  115. 115.
    Wierda W, Siddiqi T, Flinn I, et al. Phase 2 CAPTIVATE results of ibrutinib plus venetoclax in first-line chronic lymphocytic leukemia. ASCO Meeting Abstracts. 2018;Abstract 7502.Google Scholar
  116. 116.
    Rogers KA, Huang Y, ruppert AS, et al. Phase 2 study of combination obinutuzumab, ibrutinib and venetoclax in treatment naive and relapsed refractory chronic lymphocytic leukemia. ASH Annual Meeting Abstracts. 2018;Abstract 693.Google Scholar
  117. 117.
    Vo TT, Ryan J, Carrasco R, et al. Relative mitochondrial priming of myeloblasts and normal HSCs determines chemotherapeutic success in AML. Cell. 2012;151(2):344–55.PubMedPubMedCentralGoogle Scholar
  118. 118.
    Niu X, Wang G, Wang Y, et al. Acute myeloid leukemia cells harboring MLL fusion genes or with the acute promyelocytic leukemia phenotype are sensitive to the Bcl-2-selective inhibitor ABT-199. Leukemia. 2014;28(7):1557–60.PubMedPubMedCentralGoogle Scholar
  119. 119.
    Pan R, Hogdal LJ, Benito JM, 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.PubMedGoogle Scholar
  120. 120.
    Chan SM, Thomas D, Corces-Zimmerman MR, et al. Isocitrate dehydrogenase 1 and 2 mutations induce BCL-2 dependence in acute myeloid leukemia. Nat Med. 2015;21(2):178–84.PubMedPubMedCentralGoogle Scholar
  121. 121.
    Konopleva M, Pollyea DA, Potluri J, 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.PubMedPubMedCentralGoogle Scholar
  122. 122.
    DiNardo CD, Pratz K, Pullarkat V, et al. Venetoclax combined with decitabine or azacitidine in treatment-naive, elderly patients with acute myeloid leukemia. Blood. 2019;133:7–17.PubMedPubMedCentralGoogle Scholar
  123. 123.
    Davids MS, Roberts AW, Seymour JF, et al. Phase I first-in-human study of venetoclax in patients with relapsed or refractory non-Hodgkin lymphoma. J Clin Oncol. 2017;35(8):826–33.PubMedPubMedCentralGoogle Scholar
  124. 124.
    de Vos S, Swinnen LJ, Wang D, et al. Venetoclax, bendamustine, and rituximab in patients with relapsed or refractory NHL: a phase Ib dose-finding study. Ann Oncol. 2018;29(9):1932–8.PubMedPubMedCentralGoogle Scholar
  125. 125.
    Tam CS, Anderson MA, Pott C, et al. Ibrutinib plus venetoclax for the treatment of mantle-cell lymphoma. N Engl J Med. 2018;378(13):1211–23.PubMedPubMedCentralGoogle Scholar
  126. 126.
    Derenne S, Monia B, Dean NM, et al. Antisense strategy shows that Mcl-1 rather than Bcl-2 or Bcl-x(L) is an essential survival protein of human myeloma cells. Blood. 2002;100(1):194–9.PubMedGoogle Scholar
  127. 127.
    Wuilleme-Toumi S, Robillard N, Gomez P, et al. Mcl-1 is overexpressed in multiple myeloma and associated with relapse and shorter survival. Leukemia. 2005;19(7):1248–52.PubMedGoogle Scholar
  128. 128.
    Matulis SM, Gupta VA, Nooka AK, et al. Dexamethasone treatment promotes Bcl-2 dependence in multiple myeloma resulting in sensitivity to venetoclax. Leukemia. 2016;30(5):1086–93.PubMedGoogle Scholar
  129. 129.
    Kaufman JL, Gasparetto CJ, Mikhael J, et al. Phase 1 study of venetoclax in combination with dexamethasone as targeted therapy for t(11;14) relapsed refractory multiple myeloma. Blood. 2017;130(Suppl 1):3131.Google Scholar
  130. 130.
    Moreau P, Chanan-Khan A, Roberts AW, et al. Promising efficacy and acceptable safety of venetoclax plus bortezomib and dexamethasone in relapsed/refractory MM. Blood. 2017;130(22):2392–400.PubMedGoogle Scholar
  131. 131.
    Vogler M. Targeting BCL2-Proteins for the treatment of solid tumours. Adv Med. 2014;2014:943648.PubMedCentralGoogle Scholar
  132. 132.
    Beroukhim R, Mermel CH, Porter D, et al. The landscape of somatic copy-number alteration across human cancers. Nature. 2010;463(7283):899–905.PubMedPubMedCentralGoogle Scholar
  133. 133.
    Lessene G, Czabotar PE, Sleebs BE, et al. Structure-guided design of a selective BCL-X(L) inhibitor. Nat Chem Biol. 2013;9(6):390–7.PubMedGoogle Scholar
  134. 134.
    Zhang H, Xue J, Hessler P, et al. Genomic analysis and selective small molecule inhibition identifies BCL-X(L) as a critical survival factor in a subset of colorectal cancer. Mol Cancer. 2015;14:126.PubMedPubMedCentralGoogle Scholar
  135. 135.
    Tao ZF, Hasvold L, Wang L, et al. Discovery of a potent and selective BCL-XL inhibitor with in vivo activity. ACS Med Chem Lett. 2014;5(10):1088–93.PubMedPubMedCentralGoogle Scholar
  136. 136.
    LaBelle JL, Katz SG, Bird GH, et al. A stapled BIM peptide overcomes apoptotic resistance in hematologic cancers. J Clin Investig. 2012;122(6):2018–31.PubMedGoogle Scholar
  137. 137.
    Campbell KJ, Dhayade S, Ferrari N, et al. MCL-1 is a prognostic indicator and drug target in breast cancer. Cell Death Dis. 2018;9(2):19.PubMedPubMedCentralGoogle Scholar
  138. 138.
    Young AI, Law AM, Castillo L, et al. MCL-1 inhibition provides a new way to suppress breast cancer metastasis and increase sensitivity to dasatinib. Breast Cancer Res. 2016;18(1):125.PubMedPubMedCentralGoogle Scholar
  139. 139.
    Wertz IE, Kusam S, Lam C, et al. Sensitivity to antitubulin chemotherapeutics is regulated by MCL1 and FBW7. Nature. 2011;471(7336):110–4.PubMedGoogle Scholar
  140. 140.
    Wei SH, Dong K, Lin F, et al. Inducing apoptosis and enhancing chemosensitivity to gemcitabine via RNA interference targeting Mcl-1 gene in pancreatic carcinoma cell. Cancer Chemother Pharmacol. 2008;62(6):1055–64.PubMedGoogle Scholar
  141. 141.
    Konopleva M, Contractor R, Tsao T, 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.PubMedGoogle Scholar
  142. 142.
    Keuling AM, Felton KE, Parker AA, Akbari M, Andrew SE, Tron VA. RNA silencing of Mcl-1 enhances ABT-737-mediated apoptosis in melanoma: role for a caspase-8-dependent pathway. PLoS One. 2009;4(8):e6651.PubMedPubMedCentralGoogle Scholar
  143. 143.
    Kang MH, Wan Z, Kang YH, Sposto R, Reynolds CP. Mechanism of synergy of N-(4-hydroxyphenyl)retinamide and ABT-737 in acute lymphoblastic leukemia cell lines: Mcl-1 inactivation. J Natl Cancer Inst. 2008;100(8):580–95.PubMedGoogle Scholar
  144. 144.
    Leverson JD, Zhang H, Chen J, et al. Potent and selective small-molecule MCL-1 inhibitors demonstrate on-target cancer cell killing activity as single agents and in combination with ABT-263 (navitoclax). Cell Death Dis. 2015;6:e1590.PubMedPubMedCentralGoogle Scholar
  145. 145.
    Kotschy A, Szlavik Z, Murray J, et al. The MCL1 inhibitor S63845 is tolerable and effective in diverse cancer models. Nature. 2016;538(7626):477–82.PubMedPubMedCentralGoogle Scholar
  146. 146.
    Certo M, Del Gaizo Moore V, Nishino M, et al. Mitochondria primed by death signals determine cellular addiction to antiapoptotic BCL-2 family members. Cancer Cell. 2006;9(5):351–65.PubMedGoogle Scholar
  147. 147.
    Deng J, Carlson N, Takeyama K, Dal Cin P, Shipp M, Letai A. BH3 profiling identifies three distinct classes of apoptotic blocks to predict response to ABT-737 and conventional chemotherapeutic agents. Cancer Cell. 2007;12(2):171–85.PubMedGoogle Scholar
  148. 148.
    Ryan J, Letai A. BH3 profiling in whole cells by fluorimeter or FACS. Methods. 2013;61(2):156–64.PubMedPubMedCentralGoogle Scholar
  149. 149.
    Montero J, Sarosiek KA, DeAngelo JD, et al. Drug-induced death signaling strategy rapidly predicts cancer response to chemotherapy. Cell. 2015;160(5):977–89.PubMedPubMedCentralGoogle Scholar
  150. 150.
    Tahir SK, Smith ML, Hessler P, et al. Potential mechanisms of resistance to venetoclax and strategies to circumvent it. BMC Cancer. 2017;17(1):399.PubMedPubMedCentralGoogle Scholar
  151. 151.
    Fresquet V, Rieger M, Carolis C, Garcia-Barchino MJ, Martinez-Climent JA. Acquired mutations in BCL2 family proteins conferring resistance to the BH3 mimetic ABT-199 in lymphoma. Blood. 2014;123(26):4111–9.PubMedGoogle Scholar
  152. 152.
    Blombery P, Anderson MA, Gong JN, et al. Acquisition of the recurrent Gly101Val mutation in BCL2 confers resistance to venetoclax in patients with progressive chronic lymphocytic leukemia. Cancer Discov. 2019;9:342–53.PubMedGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  1. 1.Department of LeukemiaThe University of Texas MD Anderson Cancer CenterHoustonUSA

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