Why do BCL-2 inhibitorswork and where should we use them in the clinic?

Cell Death and Differentiation

Volumn 25, Issue 1, 2018, Pages 56-64

  Montero, Joan ^a,b   Letai, Antony ^a  

^a HARVARD MEDICAL SCHOOL   (United States)

^b INSTITUTE FOR BIOENGINEERING OF CATALONIA IBEC   (Spain)

Author keywords

[No Author keywords available]

Indexed keywords

2 AMINO 6 BROMO 4 (1 CYANO 2 ETHOXY 2 OXOETHYL) 4H CHROMENE 3 CARBOXYLIC ACID ETHYL ESTER; 4 [4 (4' CHLORO 2 BIPHENYLYLMETHYL) 1 PIPERAZINYL] N [4 [3 DIMETHYLAMINO 1 (PHENYLTHIOMETHYL)PROPYLAMINO] 3 NITROBENZENESULFONYL]BENZAMIDE; ANTINEOPLASTIC AGENT; BCL2 RELATED PROTEIN A1; BH3 PROTEIN; BIM PROTEIN; BRENTUXIMAB VEDOTIN; CISPLATIN; GEMCITABINE; IBRUTINIB; JANUS KINASE 2 INHIBITOR; NAVITOCLAX; OBATOCLAX; PROTEIN BAK; PROTEIN BAX; PROTEIN BCL 2; PROTEIN BCL 2 INHIBITOR; PROTEIN BCL W; PROTEIN BCL XL; PROTEIN BID; PROTEIN INHIBITOR; PROTEIN MCL 1; S 63845; UNCLASSIFIED DRUG; VENETOCLAX; APOPTOSIS REGULATORY PROTEIN; BCL2 PROTEIN, HUMAN;

ANTINEOPLASTIC ACTIVITY; ARTICLE; CANCER CELL; CELL FATE; CHRONIC LYMPHATIC LEUKEMIA; DRUG EFFICACY; DRUG MECHANISM; DRUG POTENTIATION; DRUG SAFETY; DRUG SELECTIVITY; DRUG TARGETING; HODGKIN DISEASE; HUMAN; NON SMALL CELL LUNG CANCER; NONHUMAN; PRIORITY JOURNAL; PROTEIN PROTEIN INTERACTION; SMALL CELL LUNG CANCER; SOLID MALIGNANT NEOPLASM; THROMBOCYTOPENIA; TUMOR LYSIS SYNDROME; ANTAGONISTS AND INHIBITORS; APOPTOSIS; CELL MEMBRANE PERMEABILITY; METABOLISM; MITOCHONDRIAL MEMBRANE; NEOPLASM; PHYSIOLOGY;

ANTINEOPLASTIC AGENTS; APOPTOSIS; APOPTOSIS REGULATORY PROTEINS; CELL MEMBRANE PERMEABILITY; HUMANS; MITOCHONDRIAL MEMBRANES; NEOPLASMS; PROTO-ONCOGENE PROTEINS C-BCL-2;

EID: 85044087689     PISSN: 13509047     EISSN: 14765403     Source Type: Journal    
DOI: 10.1038/cdd.2017.183     Document Type: Article

References (129)

1. Kerr JF, Wyllie AH, Currie AR. Apoptosis: A basic biological phenomenon with wide-ranging implications in tissue kinetics. Br J Cancer 1972; 26: 239-257.
2. Elmore S. Apoptosis: A review of programmed cell death. Toxicol Pathol 2007; 35: 495-516.
3. Green DR. Cell death and the immune system: Getting to how and why. Immunol Rev 2017; 277: 4-8.
4. Zou H, Li Y, Liu X, Wang X. An APAF-1.cytochrome c multimeric complex is a functional apoptosome that activates procaspase-9. J Biol Chem 1999; 274: 11549-11556.
5. McDonnell TJ, Korsmeyer SJ. Progression from lymphoid hyperplasia to high-grade malignant lymphoma in mice transgenic for the t(14; 18). Nature 1991; 349: 254-256.
6. 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: 440-442.
7. Hockenbery D, Nunez G, Milliman C, Schreiber RD, Korsmeyer SJ. Bcl-2 is an inner mitochondrial membrane protein that blocks programmed cell death. Nature 1990; 348: 334-336.
8. Strasser A, Harris AW, Bath ML, Cory S. Novel primitive lymphoid tumours induced in transgenic mice by cooperation between myc and bcl-2. Nature 1990; 348: 331-333.
9. Oltvai ZN, Milliman CL, Korsmeyer SJ. Bcl-2 heterodimerizes in vivo with a conserved homolog, Bax, that accelerates programmed cell death. Cell 1993; 74: 609-619.
10. Boise LH, Gonzalez-Garcia M, Postema CE, Ding L, Lindsten T, Turka LA et al. bcl-x, a bcl-2-related gene that functions as a dominant regulator of apoptotic cell death. Cell 1993; 74: 597-608.
11. Kozopas KM, Yang T, Buchan HL, Zhou P, Craig RW. MCL1, a gene expressed in programmed myeloid cell differentiation, has sequence similarity to BCL2. Proc Natl Acad Sci USA 1993; 90: 3516-3520.
12. Lin EY, Orlofsky A, Wang HG, Reed JC, Prystowsky MB. A1, a Bcl-2 family member, prolongs cell survival and permits myeloid differentiation. Blood 1996; 87: 983-992.
13. O'Connor L, Strasser A, O'Reilly LA, Hausmann G, Adams JM, Cory S et al. Bim: A novel member of the Bcl-2 family that promotes apoptosis. EMBO J 1998; 17: 384-395.
14. Kluck RM, Bossy-Wetzel E, Green DR, Newmeyer DD. The release of cytochrome c from mitochondria: A primary site for Bcl-2 regulation of apoptosis. Science 1997; 275: 1132-1136.
15. Liu X, Kim CN, Yang J, Jemmerson R, Wang X. Induction of apoptotic program in cell-free extracts: Requirement for dATP and cytochrome c. Cell 1996; 86: 147-157.
16. Yang J, Liu X, Bhalla K, Kim CN, Ibrado AM, Cai J et al. Prevention of apoptosis by Bcl-2: Release of cytochrome c from mitochondria blocked. Science 1997; 275: 1129-1132.
17. Bossy-Wetzel E, Newmeyer DD, Green DR. Mitochondrial cytochrome c release in apoptosis occurs upstream of DEVD-specific caspase activation and independently of mitochondrial transmembrane depolarization. EMBO J 1998; 17: 37-49.
18. Wei MC, Lindsten T, Mootha VK, Weiler S, Gross A, Ashiya M et al. tBID, a membranetargeted death ligand, oligomerizes BAK to release cytochrome c. Genes Dev 2000; 14: 2060-2071.
19. Gross A, Jockel J, Wei MC, Korsmeyer SJ. Enforced dimerization of BAX results in its translocation, mitochondrial dysfunction and apoptosis. EMBO J 1998; 17: 3878-3885.
20. Carpio MA, Michaud M, Zhou W, Fisher JK, Walensky LD, Katz SG. BCL-2 family member BOK promotes apoptosis in response to endoplasmic reticulum stress. Proc Natl Acad Sci USA 2015; 112: 7201-7206.
21. Muchmore SW, Sattler M, Liang H, Meadows RP, Harlan JE, Yoon HS et al. X-ray and NMR structure of human Bcl-xL, an inhibitor of programmed cell death. Nature 1996; 381: 335-341.
22. Wang K, Yin XM, Chao DT, Milliman CL, Korsmeyer SJ. BID: A novel BH3 domain-only death agonist. Genes Dev 1996; 10: 2859-2869.
23. Nakano K, Vousden KH. PUMA, a novel pro-apoptotic gene, is induced by p53. Mol Cell 2001; 7: 683-694.
24. Yu J, Zhang L, Hwang PM, Kinzler KW, Vogelstein B. PUMA induces the rapid apoptosis of colorectal cancer cells. Mol Cell 2001; 7: 673-682.
25. Oda E, Ohki R, Murasawa H, Nemoto J, Shibue T, Yamashita T et al. Noxa, a BH3-only member of the Bcl-2 family and candidate mediator of p53-induced apoptosis. Science 2000; 288: 1053-1058.
26. Yang E, Zha J, Jockel J, Boise LH, Thompson CB, Korsmeyer SJ. Bad, a heterodimeric partner for Bcl-XL and Bcl-2, displaces Bax and promotes cell death. Cell 1995; 80: 285-291.
27. Inohara N, Ding L, Chen S, Nunez G. harakiri, a novel regulator of cell death, encodes a protein that activates apoptosis and interacts selectively with survival-promoting proteins Bcl-2 and Bcl-X(L). EMBO J 1997; 16: 1686-1694.
28. Wei MC, Zong WX, Cheng EH, Lindsten T, Panoutsakopoulou V, Ross AJ et al. Proapoptotic BAX and BAK: A requisite gateway to mitochondrial dysfunction and death. Science 2001; 292: 727-730.
29. Lindsten T, Ross AJ, King A, Zong WX, Rathmell JC, Shiels HA et al. The combined functions of pro-apoptotic Bcl-2 family members bak and bax are essential for normal development of multiple tissues. Mol Cell 2000; 6: 1389-1399.
30. Llambi F, Wang YM, Victor B, Yang M, Schneider DM, Gingras S et al. BOK is a noncanonical BCL-2 family effector of apoptosis regulated by ER-associated degradation. Cell 2016; 165: 421-433.
31. Fernandez-Marrero Y, Ke F, Echeverry N, Bouillet P, Bachmann D, Strasser A et al. Is BOK required for apoptosis induced by endoplasmic reticulum stress?. Proc Natl Acad Sci USA 2016; 113: E492-E493.
32. Ke F, Voss A, Kerr JB, O'Reilly LA, Tai L, Echeverry N et al. BCL-2 family member BOK is widely expressed but its loss has only minimal impact in mice. Cell Death Differ 2012; 19: 915-925.
33. Merino D, Giam M, Hughes PD, Siggs OM, Heger K, O'Reilly LA et al. The role of BH3-only protein Bim extends beyond inhibiting Bcl-2-like prosurvival proteins. J Cell Biol 2009; 186: 355-362.
34. Sarosiek KA, Chi X, Bachman JA, Sims JJ, Montero J, Patel L et al. BID preferentially activates BAK while BIM preferentially activates BAX, affecting chemotherapy response. Mol Cell 2013; 51: 751-765.
35. Chen HC, Kanai M, Inoue-Yamauchi A, Tu HC, Huang Y, Ren D et al. An interconnected hierarchical model of cell death regulation by the BCL-2 family. Nat Cell Biol 2015; 17: 1270-1281.
36. Dai H, Smith A, Meng XW, Schneider PA, Pang YP, Kaufmann SH. Transient binding of an activator BH3 domain to the Bak BH3-binding groove initiates Bak oligomerization. J Cell Biol 2011; 194: 39-48.
37. Kim H, Rafiuddin-Shah M, Tu HC, Jeffers JR, Zambetti GP, Hsieh JJ et al. Hierarchical regulation of mitochondrion-dependent apoptosis by BCL-2 subfamilies. Nat Cell Biol 2006; 8: 1348-1358.
38. Du H, Wolf J, Schafer B, Moldoveanu T, Chipuk JE, Kuwana T. BH3 domains other than Bim and Bid can directly activate Bax/Bak. J Biol Chem 2011; 286: 491-501.
39. Antonsson B, Montessuit S, Sanchez B, Martinou JC. Bax is present as a high molecular weight oligomer/complex in the mitochondrial membrane of apoptotic cells. J Biol Chem 2001; 276: 11615-11623.
40. Czabotar PE, Westphal D, Dewson G, Ma S, Hockings C, Fairlie WD et al. Bax crystal structures reveal how BH3 domains activate Bax and nucleate its oligomerization to induce apoptosis. Cell 2013; 152: 519-531.
41. Mikhailov V, Mikhailova M, Degenhardt K, Venkatachalam MA, White E, Saikumar P. Association of Bax and Bak homo-oligomers in mitochondria. Bax requirement for Bak reorganization and cytochrome c release. J Biol Chem 2003; 278: 5367-5376.
42. Certo M, Del Gaizo Moore V, Nishino M, Wei G, Korsmeyer S, Armstrong SA et al. Mitochondria primed by death signals determine cellular addiction to anti-apoptotic BCL-2 family members. Cancer Cell 2006; 9: 351-365.
43. Cheng EH, Wei MC, Weiler S, Flavell RA, Mak TW, Lindsten T et al. BCL-2, BCL-X(L) sequester BH3 domain-only molecules preventing BAX- and BAK-mediated mitochondrial apoptosis. Mol Cell 2001; 8: 705-711.
44. Letai A, Bassik MC, Walensky LD, Sorcinelli MD, Weiler S, Korsmeyer SJ. Distinct BH3 domains either sensitize or activate mitochondrial apoptosis, serving as prototype cancer therapeutics. Cancer Cell 2002; 2: 183-192.
45. Willis SN, Chen L, Dewson G, Wei A, Naik E, Fletcher JI et al. Pro-apoptotic Bak is sequestered by Mcl-1 and Bcl-xL, but not Bcl-2, until displaced by BH3-only proteins. Genes Dev 2005; 19: 1294-1305.
46. Willis SN, Fletcher JI, Kaufmann T, van Delft MF, Chen L, Czabotar PE et al. Apoptosis initiated when BH3 ligands engage multiple Bcl-2 homologs, not Bax or Bak. Science 2007; 315: 856-859.
47. Ding J, Mooers BH, Zhang Z, Kale J, Falcone D, McNichol J et al. After embedding in membranes anti-apoptotic Bcl-XL protein binds both Bcl-2 homology region 3 and helix 1 of pro-apoptotic Bax protein to inhibit apoptotic mitochondrial permeabilization. J Biol Chem 2014; 289: 11873-11896.
48. 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: 171-185.
49. Brunelle JK, Letai A. Control of mitochondrial apoptosis by the Bcl-2 family. J Cell Sci 2009; 122: 437-441.
50. Ni Chonghaile T, Sarosiek KA, Vo TT, Ryan JA, Tammareddi A, Moore Vdel G et al. Pretreatment mitochondrial priming correlates with clinical response to cytotoxic chemotherapy. Science 2011; 334: 1129-1133.
51. Sarosiek KA, Fraser C, Muthalagu N, Bhola PD, Chang W, McBrayer SK et al. Developmental regulation of mitochondrial apoptosis by c-myc governs age- and tissuespecific sensitivity to cancer therapeutics. Cancer Cell 2017; 31: 142-156.
52. Faber AC, Li D, Song Y, Liang MC, Yeap BY, Bronson RT et al. Differential induction of apoptosis in HER2 and EGFR addicted cancers following PI3K inhibition. Proc Natl Acad Sci USA 2009; 106: 19503-19508.
53. Winter PS, Sarosiek KA, Lin KH, Meggendorfer M, Schnittger S, Letai A et al. RAS signaling promotes resistance to JAK inhibitors by suppressing BAD-mediated apoptosis. Sci Signal 2014; 7: Ra122.
54. Bender A, Opel D, Naumann I, Kappler R, Friedman L, von Schweinitz D et al. PI3K inhibitors prime neuroblastoma cells for chemotherapy by shifting the balance towards pro-apoptotic Bcl-2 proteins and enhanced mitochondrial apoptosis. Oncogene 2011; 30: 494-503.
55. Ren D, Tu HC, Kim H, Wang GX, Bean GR, Takeuchi O et al. BID, BIM, and PUMA are essential for activation of the BAX- and BAK-dependent cell death program. Science 2010; 330: 1390-1393.
56. Cragg MS, Kuroda J, Puthalakath H, Huang DC, Strasser A. Gefitinib-induced killing of NSCLC cell lines expressing mutant EGFR requires BIM and can be enhanced by BH3 mimetics. PLoS Med 2007; 4: 1681-1689 discussion 90.
57. Deng J, Shimamura T, Perera S, Carlson NE, Cai D, Shapiro GI et al. Pro-apoptotic BH3-only BCL-2 family protein BIM connects death signaling from epidermal growth factor receptor inhibition to the mitochondrion. Cancer Res 2007; 67: 11867-11875.
58. Kelly GL, Grabow S, Glaser SP, Fitzsimmons L, Aubrey BJ, Okamoto T et al. Targeting of MCL-1 kills MYC-driven mouse and human lymphomas even when they bear mutations in p53. Genes Dev 2014; 28: 58-70.
59. Hata AN, Yeo A, Faber AC, Lifshits E, Chen Z, Cheng KA et al. Failure to induce apoptosis via BCL-2 family proteins underlies lack of efficacy of combined MEK and PI3K inhibitors for KRAS-mutant lung cancers. Cancer Res 2014; 74: 3146-3156.
60. Hanahan D, Weinberg RA. The hallmarks of cancer. Cell 2000; 100: 57-70.
61. Hanahan D, Weinberg RA. Hallmarks of cancer: The next generation. Cell 2011; 144: 646-674.
62. Vo TT, Ryan J, Carrasco R, Neuberg D, Rossi DJ, Stone RM et al. Relative mitochondrial priming of myeloblasts and normal HSCs determines chemotherapeutic success in AML. Cell 2012; 151: 344-355.
63. Touzeau C, Ryan J, Guerriero J, Moreau P, Chonghaile TN, Le Gouill S et al. BH3 profiling identifies heterogeneous dependency on Bcl-2 family members in multiple myeloma and predicts sensitivity to BH3 mimetics. Leukemia 2016; 30: 761-764.
64. Chonghaile TN, Roderick JE, Glenfield C, Ryan J, Sallan SE, Silverman LB et al. Maturation stage of T-cell acute lymphoblastic leukemia determines BCL-2 versus BCL-XL dependence and sensitivity to ABT-199. Cancer Discov 2014; 4: 1074-1087.
65. Yecies D, Carlson NE, Deng J, Letai A. Acquired resistance to ABT-737 in lymphoma cells that up-regulate MCL-1 and BFL-1. Blood 2010; 115: 3304-3313.
66. Koss B, Morrison J, Perciavalle RM, Singh H, Rehg JE, Williams RT et al. Requirement for anti-apoptotic MCL-1 in the survival of BCR-ABL B-lineage acute lymphoblastic leukemia. Blood 2013; 122: 1587-1598.
67. Vaillant F, Merino D, Lee L, Breslin K, Pal B, Ritchie ME et al. Targeting BCL-2 with the BH3 mimetic ABT-199 in estrogen receptor-positive breast cancer. Cancer Cell 2013; 24: 120-129.
68. Potter DS, Galvin M, Brown S, Lallo A, Hodgkinson CL, Blackhall F et al. Inhibition of PI3K/BMX cell survival pathway sensitizes to BH3 mimetics in SCLC. Mol Cancer Ther 2016; 15: 1248-1260.
69. Aichberger KJ, Mayerhofer M, Krauth MT, Skvara H, Florian S, Sonneck K 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: 3303-3311.
70. Vogler M, Hamali HA, Sun XM, Bampton ET, Dinsdale D, Snowden RT et al. BCL2/BCL-X (L) inhibition induces apoptosis, disrupts cellular calcium homeostasis, and prevents platelet activation. Blood 2011; 117: 7145-7154.
71. Anderson MA, Deng J, Seymour JF, Tam C, Kim SY, Fein J et al. The BCL2 selective inhibitor venetoclax induces rapid onset apoptosis of CLL cells in patients via a TP53-independent mechanism. Blood 2016; 127: 3215-3224.
72. 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: 477-482.
73. 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: 2300-2309.
74. Del Gaizo Moore V, Brown JR, Certo M, Love TM, Novina CD, Letai A. Chronic lymphocytic leukemia requires BCL2 to sequester prodeath BIM, explaining sensitivity to BCL2 antagonist ABT-737. J Clin Invest 2007; 117: 112-121.
75. Letai A, Sorcinelli MD, Beard C, Korsmeyer SJ. Anti-apoptotic BCL-2 is required for maintenance of a model leukemia. Cancer Cell 2004; 6: 241-249.
76. Wang JL, Liu D, Zhang ZJ, Shan S, Han X, Srinivasula SM et al. Structure-based discovery of an organic compound that binds Bcl-2 protein and induces apoptosis of tumor cells. Proc Natl Acad Sci USA 2000; 97: 7124-7129.
77. 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 USA 2007; 104: 19512-19517.
78. 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: 3413-3420.
79. Paik PK, Rudin CM, Pietanza MC, Brown A, Rizvi NA, Takebe N et al. A phase II study of obatoclax mesylate, a Bcl-2 antagonist, plus topotecan in relapsed small cell lung cancer. Lung Cancer 2011; 74: 481-485.
80. Oltersdorf T, Elmore SW, Shoemaker AR, Armstrong RC, Augeri DJ, Belli BA et al. An inhibitor of Bcl-2 family proteins induces regression of solid tumours. Nature 2005; 435: 677-681.
81. 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: 389-399.
82. Zhang H, Nimmer PM, Tahir SK, Chen J, Fryer RM, Hahn KR et al. Bcl-2 family proteins are essential for platelet survival. Cell Death Differ 2007; 14: 943-951.
83. Schoenwaelder SM, Jarman KE, Gardiner EE, Hua M, Qiao J, White MJ et al. Bcl-xLinhibitory BH3 mimetics can induce a transient thrombocytopathy that undermines the hemostatic function of platelets. Blood 2011; 118: 1663-1674.
84. Mason KD, Carpinelli MR, Fletcher JI, Collinge JE, Hilton AA, Ellis S et al. Programmed anuclear cell death delimits platelet life span. Cell 2007; 128: 1173-1186.
85. Wilson WH, O'Connor OA, Czuczman MS, LaCasce AS, Gerecitano JF, Leonard JP 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: 1149-1159.
86. Gandhi L, Camidge DR, Ribeiro de Oliveira M, Bonomi P, Gandara D, Khaira D et al. Phase I study of Navitoclax (ABT-263), a novel Bcl-2 family inhibitor, in patients with small-cell lung cancer and other solid tumors. J Clin Oncol 2011; 29: 909-916.
87. Tolcher AW, LoRusso P, Arzt J, Busman TA, Lian G, Rudersdorf NS et al. Safety, efficacy, and pharmacokinetics of navitoclax (ABT-263) in combination with irinotecan: Results of an open-label, phase 1 study. Cancer Chemother Pharmacol 2015; 76: 1041-1049.
88. Kipps TJ, Eradat H, Grosicki S, Catalano J, Cosolo W, Dyagil IS 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: 2826-2833.
89. 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: 202-208.
90. Roberts AW, Davids MS, Pagel JM, Kahl BS, Puvvada SD, Gerecitano JF et al. Targeting BCL2 with venetoclax in relapsed chronic lymphocytic leukemia. N Engl J Med 2016; 374: 311-322.
91. Stilgenbauer S, Eichhorst B, Schetelig J, Coutre S, Seymour JF, Munir T et al. Venetoclax in relapsed or refractory chronic lymphocytic leukaemia with 17p deletion: A multicentre, open-label, phase 2 study. Lancet Oncol 2016; 17: 768-778.
92. 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: 1106-1117.
93. Pratz K, Pollyea D, Jonas B, Pullarkat V, Wei A, Arellano M et al. Safety and efficacy of venetoclax in combination with decitabine or azacitidine in treatment-naive, elderly patients ≥65 years with acute myeloid leukemia. Eur Hematol Assoc Madrid, Spain 2017.
94. Sarosiek KA, Letai A. Directly targeting the mitochondrial pathway of apoptosis for cancer therapy using BH3 mimetics - recent successes, current challenges and future promise. FEBS J 2016; 283: 3523-3533.
95. Wong M, Tan N, Zha J, Peale FV, Yue P, Fairbrother WJ et al. Navitoclax (ABT-263) reduces Bcl-x(L)-mediated chemoresistance in ovarian cancer models. Mol Cancer Ther 2012; 11: 1026-1035.
96. Heere-Ress E, Thallinger C, Lucas T, Schlagbauer-Wadl H, Wacheck V, Monia BP et al. Bcl-X(L) is a chemoresistance factor in human melanoma cells that can be inhibited by antisense therapy. Int J Cancer 2002; 99: 29-34.
97. Rudin CM, Hann CL, Garon EB, Ribeiro de Oliveira M, Bonomi PD, Camidge DR et al. Phase II study of single-agent navitoclax (ABT-263) and biomarker correlates in patients with relapsed small cell lung cancer. Clin Cancer Res 2012; 18: 3163-3169.
98. Zhang H, Guttikonda S, Roberts L, Uziel T, Semizarov D, Elmore SW et al. Mcl-1 is critical for survival in a subgroup of non-small-cell lung cancer cell lines. Oncogene 2011; 30: 1963-1968.
99. Derenne S, Monia B, Dean NM, Taylor JK, Rapp MJ, Harousseau JL 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: 194-199.
100. Sieghart W, Losert D, Strommer S, Cejka D, Schmid K, Rasoul-Rockenschaub S et al. Mcl-1 overexpression in hepatocellular carcinoma: A potential target for antisense therapy. J Hepatol 2006; 44: 151-157.
101. 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: 120-125.
102. Opferman JT, Letai A, Beard C, Sorcinelli MD, Ong CC, Korsmeyer SJ. Development and maintenance of B and T lymphocytes requires anti-apoptotic MCL-1. Nature 2003; 426: 671-676.
103. Wang X, Bathina M, Lynch J, Koss B, Calabrese C, Frase S et al. Deletion of MCL-1 causes lethal cardiac failure and mitochondrial dysfunction. Genes Dev 2013; 27: 1351-1364.
104. Perciavalle RM, Stewart DP, Koss B, Lynch J, Milasta S, Bathina M et al. Anti-apoptotic MCL-1 localizes to the mitochondrial matrix and couples mitochondrial fusion to respiration. Nat Cell Biol 2012; 14: 575-583.
105. Friberg A, Vigil D, Zhao B, Daniels RN, Burke JP, Garcia-Barrantes PM et al. Discovery of potent myeloid cell leukemia 1 (Mcl-1) inhibitors using fragment-based methods and structure-based design. J Med Chem 2013; 56: 15-30.
106. Stewart ML, Fire E, Keating AE, Walensky LD. The MCL-1 BH3 helix is an exclusive MCL-1 inhibitor and apoptosis sensitizer. Nat Chem Biol 2010; 6: 595-601.
107. Leverson JD, Zhang H, Chen J, Tahir SK, Phillips DC, Xue 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.
108. Letai A. S63845, an MCL-1 selective BH3 mimetic: Another arrow in our quiver. Cancer Cell 2016; 30: 834-835.
109. Vogler M, Butterworth M, Majid A, Walewska RJ, Sun XM, Dyer MJ et al. Concurrent upregulation of BCL-XL and BCL2A1 induces approximately 1000-fold resistance to ABT-737 in chronic lymphocytic leukemia. Blood 2009; 113: 4403-4413.
110. Morales AA, Kurtoglu M, Matulis SM, Liu J, Siefker D, Gutman DM et al. Distribution of Bim determines Mcl-1 dependence or codependence with Bcl-xL/Bcl-2 in Mcl-1-expressing myeloma cells. Blood 2011; 118: 1329-1339.
111. Ryan J, Letai A. BH3 profiling in whole cells by fluorimeter or FACS. Methods 2013; 61: 156-164.
112. Ryan J, Montero J, Rocco J, Letai A. iBH3: Simple, fixable BH3 profiling to determine apoptotic priming in primary tissue by flow cytometry. Biol Chem 2016; 397: 671-678.
113. Ryan JA, Brunelle JK, Letai A. Heightened mitochondrial priming is the basis for apoptotic hypersensitivity of CD4+ CD8+ thymocytes. Proc Natl Acad Sci USA 2010; 107: 12895-12900.
114. Foight GW, Ryan JA, Gulla SV, Letai A, Keating AE. Designed BH3 peptides with high affinity and specificity for targeting Mcl-1 in cells. ACS Chem Biol 2014; 9: 1962-1968.
115. 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: 362-375.
116. Benito JM, Godfrey L, Kojima K, Hogdal L, Wunderlich M, Geng H et al. MLL-rearranged acute lymphoblastic leukemias activate BCL-2 through H3K79 methylation and are sensitive to the BCL-2-specific antagonist ABT-199. Cell Rep 2015; 13: 2715-2727.
117. Montero J, Stephansky J, Cai T, Griffin GK, Cabal-Hierro L, Togami K et al. Blastic plasmacytoid dendritic cell neoplasm is dependent on BCL2 and sensitive to venetoclax. Cancer Discov 2017; 7: 156-164.
118. Anderson NM, Harrold I, Mansour MR, Sanda T, McKeown M, Nagykary N et al. BCL2-specific inhibitor ABT-199 synergizes strongly with cytarabine against the early immature LOUCY cell line but not more-differentiated T-ALL cell lines. Leukemia 2014; 28: 1145-1148.
119. Montero J, Sarosiek KA, DeAngelo JD, Maertens O, Ryan J, Ercan D et al. Drug-induced death signaling strategy rapidly predicts cancer response to chemotherapy. Cell 2015; 160: 977-989.
120. Etchin J, Montero J, Berezovskaya A, Le BT, Kentsis A, Christie AL et al. Activity of a selective inhibitor of nuclear export, selinexor (KPT-330), against AML-initiating cells engrafted into immunosuppressed NSG mice. Leukemia 2015; 30: 190-199.
121. Townsend EC, Murakami MA, Christodoulou A, Christie AL, Koster J, DeSouza TA et al. The public repository of xenografts enables discovery and randomized phase II-like trials in mice. Cancer Cell 2016; 30: 183.
122. Wu SC, Li LS, Kopp N, Montero J, Chapuy B, Yoda A et al. Activity of the type II JAK2 inhibitor CHZ868 in B cell acute lymphoblastic leukemia. Cancer Cell 2015; 28: 29-41.
123. Cleary JM, Lima CM, Hurwitz HI, Montero AJ, Franklin C, Yang J et al. A phase I clinical trial of navitoclax, a targeted high-affinity Bcl-2 family inhibitor, in combination with gemcitabine in patients with solid tumors. Invest New Drugs 2014; 32: 937-945.
124. Ju W, Zhang M, Wilson KM, Petrus MN, Bamford RN, Zhang X et al. Augmented efficacy of brentuximab vedotin combined with ruxolitinib and/or Navitoclax in a murine model of human Hodgkin's lymphoma. Proc Natl Acad Sci USA 2016; 113: 1624-1629.
125. Will B, Siddiqi T, Jorda MA, Shimamura T, Luptakova K, Staber PB et al. Apoptosis induced by JAK2 inhibition is mediated by Bim and enhanced by the BH3 mimetic ABT-737 in JAK2 mutant human erythroid cells. Blood 2010; 115: 2901-2909.
126. Kim EY, Jung JY, Kim A, Chang YS, Kim SK. ABT-737 synergizes with cisplatin bypassing aberration of apoptotic pathway in non-small Cell lung cancer. Neoplasia 2017; 19: 354-363.
127. Deng J, Isik E, Fernandes SM, Brown JR, Letai A, Davids MS. Bruton's tyrosine kinase inhibition increases BCL-2 dependence and enhances sensitivity to venetoclax in chronic lymphocytic leukemia. Leukemia 2017; 31: 2075-2084.
128. Panayotopoulou EG, Muller AK, Borries M, Busch H, Hu G, Lev S. Targeting of apoptotic pathways by SMAC or BH3 mimetics distinctly sensitizes paclitaxel-resistant triple negative breast cancer cells. Oncotarget 2017.
129. Kuroda J, Puthalakath H, Cragg MS, Kelly PN, Bouillet P, Huang DC et al. Bim and Bad mediate imatinib-induced killing of Bcr/Abl+ leukemic cells, and resistance due to their loss is overcome by a BH3 mimetic. Proc Natl Acad Sci USA 2006; 103: 14907-14912