Sensitivity and Resistance to BH3 Mimetics in Cancer Therapy

  • Konstantinos V. Floros
  • Anthony C. Faber
  • Hisashi Harada
Chapter
Part of the Resistance to Targeted Anti-Cancer Therapeutics book series (RTACT, volume 15)

Abstract

Targeted molecular agents have revolutionized cancer care in the adult population. Many of these drugs have been inhibitors of kinases. BCL-2 family members have long been understood to play key roles in mitochondrial integrity, serving as the key signaling nexus between kinase cascade-driven growth and survival signals, and they can also be found genetically altered in human cancers (e.g. IgG-BCL-2 translocations in follicular lymphoma). Indeed, the FDA-approval of the BCL-2 homology (BH)3 domain mimetic, venetoclax (AbbVie), is the first clinically approved BCL-2 family member targeted therapy of any kind, bringing BCL-2 family member inhibitors into the spotlight. This chapter will highlight the current state of affairs of this exciting time for BCL-2 family member targeted therapies, by focusing on three most advanced types of BCL-2 family inhibitors: the BCL-2 BH3 mimetic, venetoclax; the dual BCL-2/BCL-xL BH3 mimetic, navitoclax; and the recently developed MCL-1 BH3 mimetics. We will also discuss resistant mechanisms that have emerged from the intensification of preclinical and clinical studies of these compounds. The challenges understanding which cancers may most benefit from BH3 mimetics will also be discussed, as will the emergence of BH3 profling to address these challenges. Finally, we will discuss how these drugs may be combined with other currently available drugs to overcome resistance and induce robust clinical responses.

Keywords

BH3 mimetics Resistance Targeted therapies Apoptosis Venetoclax Navitoclax 

Abbreviations

ALK

Anaplastic lymphoma kinase

BAX

BCL-2 associated X protein

BCL-2

B cell-lymphoma 2

BH3

BCL-2 homology 3

BIM

BCL-2 interacting mediator of cell death

BRAF

V-Raf murine sarcoma viral oncogene homolog B

EGFR

Epidermal growth factor receptor

HER2

Proto-oncogene Neu

MCL-1

Myeloid cell leukemia-1

MEK

Mitogen-activated protein kinase kinase

MOMP

Mitochondrial Outer Membrane Permeabilization

mTOR

Mechanistic target of repamycin

MYCN

V-myc avian myelocytomatosis viral oncogene neuroblastoma derived homolog

PI3K

Phosphoinositide 3-kinase

PUMA

p53 upregulated modulator of apoptosis

Notes

Acknowledgments

This review was partly funded by NIH/NCI grant 5K22CA175276 (ACF), an American Cancer Society Research Scholar Grant (ACF), and a Massey Cancer Center Pilot grant (HH and ACF).

Conflict of Interest

No potential conflicts of interest were disclosed.

Note added in proof

We recently published that venetoclax is effective in small cell lung cancer with high BCL-2 expression [168], which, for the first time, demonstrates the eff ect of venetoclax in solid tumors.

References

  1. 1.
    Degli Esposti M. Bioenergetic evolution in proteobacteria and mitochondria. Genome Biol Evol. 2014;6:3238–51.CrossRefPubMedPubMedCentralGoogle Scholar
  2. 2.
    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;348:331–3.CrossRefPubMedGoogle Scholar
  3. 3.
    Hanahan D, Weinberg RA. The hallmarks of cancer. Cell. 2000;100:57–70.CrossRefPubMedGoogle Scholar
  4. 4.
    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;12:171–85.CrossRefPubMedGoogle Scholar
  5. 5.
    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;2:183–92.CrossRefPubMedGoogle Scholar
  6. 6.
    Kim H, Tu HC, Ren D, Takeuchi O, Jeffers JR, Zambetti GP, Hsieh JJ, Cheng EH. Stepwise activation of BAX and BAK by tBID, BIM, and PUMA initiates mitochondrial apoptosis. Mol Cell. 2009;36:487–99.CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Kim H, Rafiuddin-Shah M, Tu HC, Jeffers JR, Zambetti GP, Hsieh JJ, Cheng EH. Hierarchical regulation of mitochondrion-dependent apoptosis by BCL-2 subfamilies. Nat Cell Biol. 2006;8:1348–58.CrossRefPubMedGoogle Scholar
  8. 8.
    Chen L, Willis SN, Wei A, Smith BJ, Fletcher JI, Hinds MG, Colman PM, Day CL, Adams JM, Huang DC. Differential targeting of prosurvival Bcl-2 proteins by their BH3-only ligands allows complementary apoptotic function. Mol Cell. 2005;17:393–403.CrossRefPubMedGoogle Scholar
  9. 9.
    Willis SN, Fletcher JI, Kaufmann T, van Delft MF, Chen L, Czabotar PE, Ierino H, Lee EF, Fairlie WD, Bouillet P, Strasser A, Kluck RM, Adams JM, Huang DC. Apoptosis initiated when BH3 ligands engage multiple Bcl-2 homologs, not Bax or Bak. Science. 2007;315:856–9.CrossRefPubMedGoogle Scholar
  10. 10.
    Willis SN, Chen L, Dewson G, Wei A, Naik E, Fletcher JI, Adams JM, Huang DC. Proapoptotic Bak is sequestered by Mcl-1 and Bcl-xL, but not Bcl-2, until displaced by BH3-only proteins. Genes Dev. 2005;19:1294–305.CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    O’Neill KL, Huang K, Zhang J, Chen Y, Luo X. Inactivation of prosurvival Bcl-2 proteins activates Bax/Bak through the outer mitochondrial membrane. Genes Dev. 2016;30:973–88.CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Llambi F, Moldoveanu T, Tait SW, Bouchier-Hayes L, Temirov J, McCormick LL, Dillon CP, Green DR. A unified model of mammalian BCL-2 protein family interactions at the mitochondria. Mol Cell. 2011;44:517–31.CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Bean GR, Ganesan YT, Dong Y, Takeda S, Liu H, Chan PM, Huang Y, Chodosh LA, Zambetti GP, Hsieh JJ, Cheng EH. PUMA and BIM are required for oncogene inactivation-induced apoptosis. Sci Signal. 2013;6:ra20.CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Egle A, Harris AW, Bouillet P, Cory S. Bim is a suppressor of Myc-induced mouse B cell leukemia. Proc Natl Acad Sci U S A. 2004;101:6164–9.CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Glaser SP, Lee EF, Trounson E, Bouillet P, Wei A, Fairlie WD, Izon DJ, Zuber J, Rappaport AR, Herold MJ, Alexander WS, Lowe SW, Robb L, Strasser A. Anti-apoptotic Mcl-1 is essential for the development and sustained growth of acute myeloid leukemia. Genes Dev. 2012;26:120–5.CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Faber AC, Corcoran RB, Ebi H, Sequist LV, Waltman BA, Chung E, Incio J, Digumarthy SR, Pollack SF, Song Y, Muzikansky A, Lifshits E, Roberge S, Coffman EJ, Benes CH, Gomez HL, Baselga J, Arteaga CL, Rivera MN, Dias-Santagata D, Jain RK, Engelman JA. BIM expression in treatment-naive cancers predicts responsiveness to kinase inhibitors. Cancer Discov. 2011;1:352–65.CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Ng KP, Hillmer AM, Chuah CT, Juan WC, Ko TK, Teo AS, Ariyaratne PN, Takahashi N, Sawada K, Fei Y, Soh S, Lee WH, Huang JW, Allen JC Jr, Woo XY, Nagarajan N, Kumar V, Thalamuthu A, Poh WT, Ang AL, Mya HT, How GF, Yang LY, Koh LP, Chowbay B, Chang CT, Nadarajan VS, Chng WJ, Than H, Lim LC, Goh YT, Zhang S, Poh D, Tan P, Seet JE, Ang MK, Chau NM, Ng QS, Tan DS, Soda M, Isobe K, Nothen MM, Wong TY, Shahab A, Ruan X, Cacheux-Rataboul V, Sung WK, Tan EH, Yatabe Y, Mano H, Soo RA, Chin TM, Lim WT, Ruan Y, Ong ST. A common BIM deletion polymorphism mediates intrinsic resistance and inferior responses to tyrosine kinase inhibitors in cancer. Nat Med. 2012;18:521–8.CrossRefPubMedGoogle Scholar
  18. 18.
    Karachaliou N, Codony-Servat J, Teixido C, Pilotto S, Drozdowskyj A, Codony-Servat C, Gimenez-Capitan A, Molina-Vila MA, Bertran-Alamillo J, Gervais R, Massuti B, Moran T, Majem M, Felip E, Carcereny E, Garcia-Campelo R, Viteri S, Gonzalez-Cao M, Morales-Espinosa D, Verlicchi A, Crisetti E, Chaib I, Santarpia M, Luis Ramirez J, Bosch-Barrera J, Felipe Cardona A, de Marinis F, Lopez-Vivanco G, Miguel Sanchez J, Vergnenegre A, Sanchez Hernandez JJ, Sperduti I, Bria E, Rosell R. BIM and mTOR expression levels predict outcome to erlotinib in EGFR-mutant non-small-cell lung cancer. Sci Rep. 2015;5:17499.CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Costa C, Molina MA, Drozdowskyj A, Gimenez-Capitan A, Bertran-Alamillo J, Karachaliou N, Gervais R, Massuti B, Wei J, Moran T, Majem M, Felip E, Carcereny E, Garcia-Campelo R, Viteri S, Taron M, Ono M, Giannikopoulos P, Bivona T, Rosell R. The impact of EGFR T790M mutations and BIM mRNA expression on outcome in patients with EGFR-mutant NSCLC treated with erlotinib or chemotherapy in the randomized phase III EURTAC trial. Clin Cancer Res. 2014;20:2001–10.CrossRefPubMedGoogle Scholar
  20. 20.
    Zhao M, Zhang Y, Cai W, Li J, Zhou F, Cheng N, Ren R, Zhao C, Li X, Ren S, Zhou C, Hirsch FR. The Bim deletion polymorphism clinical profile and its relation with tyrosine kinase inhibitor resistance in Chinese patients with non-small cell lung cancer. Cancer. 2014;120:2299–307.CrossRefPubMedGoogle Scholar
  21. 21.
    Zhang L, Jiang T, Li X, Wang Y, Zhao C, Zhao S, Xi L, Zhang S, Liu X, Jia Y, Yang H, Shi J, Su C, Ren S, Zhou C. Clinical features of Bim deletion polymorphism and its relation with crizotinib primary resistance in Chinese patients with ALK/ROS1 fusion-positive non-small cell lung cancer. Cancer. 2017;123(15):2927–35.CrossRefPubMedGoogle Scholar
  22. 22.
    Wayne AS, Fitzgerald DJ, Kreitman RJ, Pastan I. Immunotoxins for leukemia. Blood. 2014;123:2470–7.CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Wu N, Huang Y, Zou Z, Gimenez-Capitan A, Yu L, Hu W, Zhu L, Sun X, Sanchez JJ, Guan W, Liu B, Rosell R, Wei J. High BIM mRNA levels are associated with longer survival in advanced gastric cancer. Oncol Lett. 2017;13:1826–34.CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Sordella R, Bell DW, Haber DA, Settleman J. Gefitinib-sensitizing EGFR mutations in lung cancer activate anti-apoptotic pathways. Science. 2004;305:1163–7.CrossRefPubMedGoogle Scholar
  25. 25.
    Faber AC, Li D, Song Y, Liang MC, Yeap BY, Bronson RT, Lifshits E, Chen Z, Maira SM, Garcia-Echeverria C, Wong KK, Engelman JA. Differential induction of apoptosis in HER2 and EGFR addicted cancers following PI3K inhibition. Proc Natl Acad Sci U S A. 2009;106:19503–8.CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Wickenden JA, Jin H, Johnson M, Gillings AS, Newson C, Austin M, Chell SD, Balmanno K, Pritchard CA, Cook SJ. Colorectal cancer cells with the BRAF(V600E) mutation are addicted to the ERK1/2 pathway for growth factor-independent survival and repression of BIM. Oncogene. 2008;27:7150–61.CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Kitai H, Ebi H, Tomida S, Floros KV, Kotani H, Adachi Y, Oizumi S, Nishimura M, Faber AC, Yano S. Epithelial-to-mesenchymal transition defines feedback activation of receptor tyrosine kinase signaling induced by MEK inhibition in KRAS-mutant lung cancer. Cancer Discov. 2016;6:754–69.CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Flaherty KT. BRAF inhibitors and melanoma. Cancer J. 2011;17:505–11.CrossRefPubMedGoogle Scholar
  29. 29.
    Katayama R, Shaw AT, Khan TM, Mino-Kenudson M, Solomon BJ, Halmos B, Jessop NA, Wain JC, Yeo AT, Benes C, Drew L, Saeh JC, Crosby K, Sequist LV, Iafrate AJ, Engelman JA. Mechanisms of acquired crizotinib resistance in ALK-rearranged lung Cancers. Sci Transl Med. 2012;4:120ra117.CrossRefGoogle Scholar
  30. 30.
    Sale MJ, Cook SJ. The BH3-mimetic ABT-263 synergises with the MEK1/2 inhibitor selumetinib/AZD6244 to promote BIM-dependent tumour cell death and inhibit acquired resistance. Biochem J. 2012;450(2):285–94.CrossRefGoogle Scholar
  31. 31.
    Anderson GR, Wardell SE, Cakir M, Crawford L, Leeds JC, Nussbaum DP, Shankar PS, Soderquist RS, Stein EM, Tingley JP, Winter PS, Zieser-Misenheimer EK, Alley HM, Yllanes A, Haney V, Blackwell KL, McCall SJ, McDonnell DP, Wood KC. PIK3CA mutations enable targeting of a breast tumor dependency through mTOR-mediated MCL-1 translation. Sci Transl Med. 2016;8:369ra175.CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Hata AN, Engelman JA, Faber AC. The BCL2 family: key mediators of the apoptotic response to targeted anticancer therapeutics. Cancer Discov. 2015;5:475–87.CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    Certo M, Del Gaizo Moore V, Nishino M, Wei G, Korsmeyer S, Armstrong SA, Letai A. Mitochondria primed by death signals determine cellular addiction to antiapoptotic BCL-2 family members. Cancer Cell. 2006;9:351–65.CrossRefPubMedGoogle Scholar
  34. 34.
    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 Investig. 2007;117:112–21.CrossRefPubMedPubMedCentralGoogle Scholar
  35. 35.
    Del Gaizo Moore V, Letai A. BH3 profiling—Measuring integrated function of the mitochondrial apoptotic pathway to predict cell fate decisions. Cancer Lett. 2012;332(2):202–5.CrossRefPubMedGoogle Scholar
  36. 36.
    Ni Chonghaile T, Sarosiek KA, Vo TT, Ryan JA, Tammareddi A, Moore Vdel G, Deng J, Anderson KC, Richardson P, Tai YT, Mitsiades CS, Matulonis UA, Drapkin R, Stone R, Deangelo DJ, McConkey DJ, Sallan SE, Silverman L, Hirsch MS, Carrasco DR, Letai A. Pretreatment mitochondrial priming correlates with clinical response to cytotoxic chemotherapy. Science. 2011;334:1129–33.CrossRefPubMedGoogle Scholar
  37. 37.
    Hata AN, Yeo A, Faber AC, Lifshits E, Chen Z, Cheng KA, Walton Z, Sarosiek KA, Letai A, Heist RS, Mino-Kenudson M, Wong KK, Engelman JA. 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;74:3146–56.CrossRefPubMedPubMedCentralGoogle Scholar
  38. 38.
    Sarosiek KA, Fraser C, Muthalagu N, Bhola PD, Chang W, McBrayer SK, Cantlon A, Fisch S, Golomb-Mello G, Ryan JA, Deng J, Jian B, Corbett C, Goldenberg M, Madsen JR, Liao R, Walsh D, Sedivy J, Murphy DJ, Carrasco DR, Robinson S, Moslehi J, Letai A. Developmental regulation of mitochondrial apoptosis by c-Myc governs age- and tissue-specific sensitivity to cancer therapeutics. Cancer Cell. 2017;31:142–56.CrossRefPubMedGoogle Scholar
  39. 39.
    Touzeau C, Ryan J, Guerriero J, Moreau P, Chonghaile TN, Le Gouill S, Richardson P, Anderson K, Amiot M, Letai A. BH3 profiling identifies heterogeneous dependency on Bcl-2 family members in multiple myeloma and predicts sensitivity to BH3 mimetics. Leukemia. 2016;30:761–4.CrossRefPubMedGoogle Scholar
  40. 40.
    Montero J, Letai A. Dynamic BH3 profiling-poking cancer cells with a stick. Mol Cell Oncol. 2016;3:e1040144.CrossRefPubMedPubMedCentralGoogle Scholar
  41. 41.
    Montero J, Sarosiek KA, DeAngelo JD, Maertens O, Ryan J, Ercan D, Piao H, Horowitz NS, Berkowitz RS, Matulonis U, Janne PA, Amrein PC, Cichowski K, Drapkin R, Letai A. Drug-induced death signaling strategy rapidly predicts cancer response to chemotherapy. Cell. 2015;160:977–89.CrossRefPubMedPubMedCentralGoogle Scholar
  42. 42.
    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;283:3523–33.CrossRefPubMedPubMedCentralGoogle Scholar
  43. 43.
    Clerc P, Carey GB, Mehrabian Z, Wei M, Hwang H, Girnun GD, Chen H, Martin SS, Polster BM. Rapid detection of an ABT-737-sensitive primed for death state in cells using microplate-based respirometry. PLoS One. 2012;7:e42487.CrossRefPubMedPubMedCentralGoogle Scholar
  44. 44.
    Lee JH, Lin YL, Hsu WH, Chen HY, Chang YC, Yu CJ, Shih JY, Lin CC, Chen KY, Ho CC, Laio WY, Yang PC, Yang JC. Bcl-2-like protein 11 deletion polymorphism predicts survival in advanced non-small-cell lung cancer. J Thorac Oncol. 2014;9:1385–92.CrossRefPubMedGoogle Scholar
  45. 45.
    Ying HQ, Chen J, He BS, Pan YQ, Wang F, Deng QW, Sun HL, Liu X, Wang SK. The effect of BIM deletion polymorphism on intrinsic resistance and clinical outcome of cancer patient with kinase inhibitor therapy. Sci Rep. 2015;5:11348.CrossRefPubMedPubMedCentralGoogle Scholar
  46. 46.
    Paraiso KH, Xiang Y, Rebecca VW, Abel EV, Chen YA, Munko AC, Wood E, Fedorenko IV, Sondak VK, Anderson AR, Ribas A, Palma MD, Nathanson KL, Koomen JM, Messina JL, Smalley KS. PTEN loss confers BRAF inhibitor resistance to melanoma cells through the suppression of BIM expression. Cancer Res. 2011;71:2750–60.CrossRefPubMedPubMedCentralGoogle Scholar
  47. 47.
    Flaherty KT, McArthur G. BRAF, a target in melanoma: implications for solid tumor drug development. Cancer. 2010;116:4902–13.CrossRefPubMedGoogle Scholar
  48. 48.
    Neal JW, Sequist LV. First-line use of EGFR tyrosine kinase inhibitors in patients with NSCLC containing EGFR mutations. Clin Adv Hematol Oncol. 2010;8:119–26.PubMedGoogle Scholar
  49. 49.
    Kwak EL, Bang YJ, Camidge DR, Shaw AT, Solomon B, Maki RG, Ou SH, Dezube BJ, Janne PA, Costa DB, Varella-Garcia M, Kim WH, Lynch TJ, Fidias P, Stubbs H, Engelman JA, Sequist LV, Tan W, Gandhi L, Mino-Kenudson M, Wei GC, Shreeve SM, Ratain MJ, Settleman J, Christensen JG, Haber DA, Wilner K, Salgia R, Shapiro GI, Clark JW, Iafrate AJ. Anaplastic lymphoma kinase inhibition in non-small-cell lung cancer. N Engl J Med. 2010;363:1693–703.CrossRefPubMedPubMedCentralGoogle Scholar
  50. 50.
    Schalk E, Neum S, Kranz S, Scheinpflug K, Mohren M. Long-term remission in a patient with BCR/ABL-positive acute myeloid leukaemia on maintenance therapy with imatinib. Leuk Res. 2009;33:e6–7.CrossRefPubMedGoogle Scholar
  51. 51.
    Eichhorn JM, Alford SE, Hughes CC, Fenical W, Chambers TC. Purported Mcl-1 inhibitor marinopyrrole A fails to show selective cytotoxicity for Mcl-1-dependent cell lines. Cell Death Dis. 2013;4:e880.CrossRefPubMedPubMedCentralGoogle Scholar
  52. 52.
    Varadarajan S, Butterworth M, Wei J, Pellecchia M, Dinsdale D, Cohen GM. Sabutoclax (BI97C1) and BI112D1, putative inhibitors of MCL-1, induce mitochondrial fragmentation either upstream of or independent of apoptosis. Neoplasia. 2013;15:568–78.CrossRefPubMedPubMedCentralGoogle Scholar
  53. 53.
    Vogler M, Weber K, Dinsdale D, Schmitz I, Schulze-Osthoff K, Dyer MJ, Cohen GM. Different forms of cell death induced by putative BCL2 inhibitors. Cell Death Differ. 2009;16:1030–9.CrossRefPubMedGoogle Scholar
  54. 54.
    Smith ML, Chyla B, McKeegan E, Tahir SK. Development of a flow cytometric method for quantification of BCL-2 family members in chronic lymphocytic leukemia and correlation with sensitivity to BCL-2 family inhibitors. Cytometry B Clin Cytom. 2016;92(5):331–9.CrossRefPubMedGoogle Scholar
  55. 55.
    Billard C. BH3 mimetics: status of the field and new developments. Molecul Cancer Therapeut. 2013;12:1691–700.CrossRefGoogle Scholar
  56. 56.
    Soderquist R, Pletnev AA, Danilov AV, Eastman A. The putative BH3 mimetic S1 sensitizes leukemia to ABT-737 by increasing reactive oxygen species, inducing endoplasmic reticulum stress, and upregulating the BH3-only protein NOXA. Apoptosis. 2014;19:201–9.CrossRefPubMedPubMedCentralGoogle Scholar
  57. 57.
    Nguyen M, Marcellus RC, Roulston A, Watson M, Serfass L, Murthy Madiraju SR, Goulet D, Viallet J, Belec L, Billot X, Acoca S, Purisima E, Wiegmans A, Cluse L, Johnstone RW, Beauparlant P, Shore GC. Small molecule obatoclax (GX15-070) antagonizes MCL-1 and overcomes MCL-1-mediated resistance to apoptosis. Proc Natl Acad Sci U S A. 2007;104:19512–7.CrossRefPubMedPubMedCentralGoogle Scholar
  58. 58.
    Rahmani M, Aust MM, Attkisson E, Williams DC Jr, Ferreira-Gonzalez A, Grant S. Inhibition of Bcl-2 antiapoptotic members by obatoclax potently enhances sorafenib-induced apoptosis in human myeloid leukemia cells through a Bim-dependent process. Blood. 2012;119:6089–98.CrossRefPubMedPubMedCentralGoogle Scholar
  59. 59.
    Hwang JJ, Kuruvilla J, Mendelson D, Pishvaian MJ, Deeken JF, Siu LL, Berger MS, Viallet J, Marshall JL. Phase I dose finding studies of obatoclax (GX15-070), a small molecule pan-BCL-2 family antagonist, in patients with advanced solid tumors or lymphoma. Clin Cancer Res. 2010;16:4038–45.CrossRefPubMedPubMedCentralGoogle Scholar
  60. 60.
    Chiappori AA, Schreeder MT, Moezi MM, Stephenson JJ, Blakely J, Salgia R, Chu QS, Ross HJ, Subramaniam DS, Schnyder J, Berger MS. A phase I trial of pan-Bcl-2 antagonist obatoclax administered as a 3-h or a 24-h infusion in combination with carboplatin and etoposide in patients with extensive-stage small cell lung cancer. Br J Cancer. 2012;106:839–45.CrossRefPubMedPubMedCentralGoogle Scholar
  61. 61.
    Tang Y, Hamed HA, Cruickshanks N, Fisher PB, Grant S, Dent P. Obatoclax and lapatinib interact to induce toxic autophagy through NOXA. Mol Pharmacol. 2012;81:527–40.CrossRefPubMedPubMedCentralGoogle Scholar
  62. 62.
    Martinez-Paniagua MA, Baritaki S, Huerta-Yepez S, Ortiz-Navarrete VF, Gonzalez-Bonilla C, Bonavida B, Vega MI. Mcl-1 and YY1 inhibition and induction of DR5 by the BH3-mimetic Obatoclax (GX15-070) contribute in the sensitization of B-NHL cells to TRAIL apoptosis. Cell Cycle. 2011;10:2792–805.CrossRefPubMedPubMedCentralGoogle Scholar
  63. 63.
    Heidari N, Hicks MA, Harada H. GX15-070 (obatoclax) overcomes glucocorticoid resistance in acute lymphoblastic leukemia through induction of apoptosis and autophagy. Cell Death Dis. 2010;1:e76.CrossRefPubMedPubMedCentralGoogle Scholar
  64. 64.
    Lessene G, Czabotar PE, Colman PM. BCL-2 family antagonists for cancer therapy. Nat Rev Drug Discov. 2008;7:989–1000.CrossRefPubMedGoogle Scholar
  65. 65.
    Tse C, Shoemaker AR, Adickes J, Anderson MG, Chen J, Jin S, Johnson EF, Marsh KC, Mitten MJ, Nimmer P, Roberts L, Tahir SK, Xiao Y, Yang X, Zhang H, Fesik S, Rosenberg SH, Elmore SW. ABT-263: a potent and orally bioavailable Bcl-2 family inhibitor. Cancer Res. 2008;68:3421–8.CrossRefPubMedGoogle Scholar
  66. 66.
    Merino D, Khaw SL, Glaser SP, Anderson DJ, Belmont LD, Wong C, Yue P, Robati M, Phipson B, Fairlie WD, Lee EF, Campbell KJ, Vandenberg CJ, Cory S, Roberts AW, Ludlam MJ, Huang DC, Bouillet P. Bcl-2, Bcl-x(L), and Bcl-w are not equivalent targets of ABT-737 and navitoclax (ABT-263) in lymphoid and leukemic cells. Blood. 2012;119:5807–16.CrossRefPubMedPubMedCentralGoogle Scholar
  67. 67.
    Al-Harbi S, Hill BT, Mazumder S, Singh K, Devecchio J, Choudhary G, Rybicki LA, Kalaycio M, Maciejewski JP, Houghton JA, Almasan A. An antiapoptotic BCL-2 family expression index predicts the response of chronic lymphocytic leukemia to ABT-737. Blood. 2011;118:3579–90.CrossRefPubMedPubMedCentralGoogle Scholar
  68. 68.
    Bodet L, Gomez-Bougie P, Touzeau C, Dousset C, Descamps G, Maiga S, Avet-Loiseau H, Bataille R, Moreau P, Le Gouill S, Pellat-Deceunynck C, Amiot M. ABT-737 is highly effective against molecular subgroups of multiple myeloma. Blood. 2011;118:3901–10.CrossRefPubMedGoogle Scholar
  69. 69.
    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;111:2300–9.CrossRefPubMedPubMedCentralGoogle Scholar
  70. 70.
    Faber AC, Farago AF, Costa C, Dastur A, Gomez-Caraballo M, Robbins R, Wagner BL, Rideout WM 3rd, Jakubik CT, Ham J, Edelman EJ, Ebi H, Yeo AT, Hata AN, Song Y, Patel NU, March RJ, Tam AT, Milano RJ, Boisvert JL, Hicks MA, Elmiligy S, Malstrom SE, Rivera MN, Harada H, Windle BE, Ramaswamy S, Benes CH, Jacks T, Engelman JA. Assessment of ABT-263 activity across a cancer cell line collection leads to a potent combination therapy for small-cell lung cancer. Proc Natl Acad Sci U S A. 2015;112(11):E1288–96.CrossRefPubMedPubMedCentralGoogle Scholar
  71. 71.
    Lock R, Carol H, Houghton PJ, Morton CL, Kolb EA, Gorlick R, Reynolds CP, Maris JM, Keir ST, Wu J, Smith MA. Initial testing (stage 1) of the BH3 mimetic ABT-263 by the pediatric preclinical testing program. Pediatr Blood Cancer. 2008;50:1181–9.CrossRefPubMedGoogle Scholar
  72. 72.
    Shoemaker AR, Mitten MJ, Adickes J, Ackler S, Refici M, Ferguson D, Oleksijew A, O’Connor JM, Wang B, Frost DJ, Bauch J, Marsh K, Tahir SK, Yang X, Tse C, Fesik SW, Rosenberg SH, Elmore SW. Activity of the Bcl-2 family inhibitor ABT-263 in a panel of small cell lung cancer xenograft models. Clin Cancer Res. 2008;14:3268–77.CrossRefPubMedGoogle Scholar
  73. 73.
    Nakajima W, Hicks MA, Tanaka N, Krystal GW, Harada H. Noxa determines localization and stability of MCL-1 and consequently ABT-737 sensitivity in small cell lung cancer. Cell Death Dis. 2014;5:e1052.CrossRefPubMedPubMedCentralGoogle Scholar
  74. 74.
    Lamers F, Schild L, den Hartog IJ, Ebus ME, Westerhout EM, Ora I, Koster J, Versteeg R, Caron HN, Molenaar JJ. Targeted BCL2 inhibition effectively inhibits neuroblastoma tumour growth. Eur J Cancer. 2012;48:3093–103.CrossRefPubMedGoogle Scholar
  75. 75.
    Ham J, Costa C, Sano R, Lochmann TL, Sennott EM, Patel NU, Dastur A, Gomez-Caraballo M, Krytska K, Hata AN, Floros KV, Hughes MT, Jakubik CT, Heisey DA, Ferrell JT, Bristol ML, March RJ, Yates C, Hicks MA, Nakajima W, Gowda M, Windle BE, Dozmorov MG, Garnett MJ, McDermott U, Harada H, Taylor SM, Morgan IM, Benes CH, Engelman JA, Mosse YP, Faber AC. Exploitation of the apoptosis-primed state of MYCN-amplified neuroblastoma to develop a potent and specific targeted therapy combination. Cancer Cell. 2016;29:159–72.CrossRefPubMedPubMedCentralGoogle Scholar
  76. 76.
    Korfi K, Smith M, Swan J, Somervaille TC, Dhomen N, Marais R. BIM mediates synergistic killing of B-cell acute lymphoblastic leukemia cells by BCL-2 and MEK inhibitors. Cell Death Dis. 2016;7:e2177.CrossRefPubMedPubMedCentralGoogle Scholar
  77. 77.
    Lin X, Morgan-Lappe S, Huang X, Li L, Zakula DM, Vernetti LA, Fesik SW, Shen Y. ‘Seed’ analysis of off-target siRNAs reveals an essential role of Mcl-1 in resistance to the small-molecule Bcl-2/Bcl-XL inhibitor ABT-737. Oncogene. 2007;26:3972–9.CrossRefPubMedGoogle Scholar
  78. 78.
    Iorio F, Knijnenburg TA, Vis DJ, Bignell GR, Menden MP, Schubert M, Aben N, Goncalves E, Barthorpe S, Lightfoot H, Cokelaer T, Greninger P, van Dyk E, Chang H, de Silva H, Heyn H, Deng X, Egan RK, Liu Q, Mironenko T, Mitropoulos X, Richardson L, Wang J, Zhang T, Moran S, Sayols S, Soleimani M, Tamborero D, Lopez-Bigas N, Ross-Macdonald P, Esteller M, Gray NS, Haber DA, Stratton MR, Benes CH, Wessels LF, Saez-Rodriguez J, McDermott U, Garnett MJ. A landscape of pharmacogenomic interactions in cancer. Cell. 2016;166:740–54.CrossRefPubMedPubMedCentralGoogle Scholar
  79. 79.
    Yang W, Soares J, Greninger P, Edelman EJ, Lightfoot H, Forbes S, Bindal N, Beare D, Smith JA, Thompson IR, Ramaswamy S, Futreal PA, Haber DA, Stratton MR, Benes C, McDermott U, Garnett MJ. Genomics of drug sensitivity in cancer (GDSC): a resource for therapeutic biomarker discovery in cancer cells. Nucleic Acids Res. 2013;41:D955–61.CrossRefPubMedGoogle Scholar
  80. 80.
    Garnett MJ, Edelman EJ, Heidorn SJ, Greenman CD, Dastur A, Lau KW, Greninger P, Thompson IR, Luo X, Soares J, Liu Q, Iorio F, Surdez D, Chen L, Milano RJ, Bignell GR, Tam AT, Davies H, Stevenson JA, Barthorpe S, Lutz SR, Kogera F, Lawrence K, McLaren-Douglas A, Mitropoulos X, Mironenko T, Thi H, Richardson L, Zhou W, Jewitt F, Zhang T, O’Brien P, Boisvert JL, Price S, Hur W, Yang W, Deng X, Butler A, Choi HG, Chang JW, Baselga J, Stamenkovic I, Engelman JA, Sharma SV, Delattre O, Saez-Rodriguez J, Gray NS, Settleman J, Futreal PA, Haber DA, Stratton MR, Ramaswamy S, McDermott U, Benes CH. Systematic identification of genomic markers of drug sensitivity in cancer cells. Nature. 2012;483:570–5.CrossRefPubMedPubMedCentralGoogle Scholar
  81. 81.
    Kurinna S, Konopleva M, Palla SL, Chen W, Kornblau S, Contractor R, Deng X, May WS, Andreeff M, Ruvolo PP. Bcl2 phosphorylation and active PKC alpha are associated with poor survival in AML. Leukemia. 2006;20:1316–9.CrossRefPubMedGoogle Scholar
  82. 82.
    Song T, Chai G, Liu Y, Yu X, Wang Z, Zhang Z. Bcl-2 phosphorylation confers resistance on chronic lymphocytic leukaemia cells to the BH3 mimetics ABT-737, ABT-263 and ABT-199 by impeding direct binding. Br J Pharmacol. 2016;173:471–83.CrossRefPubMedPubMedCentralGoogle Scholar
  83. 83.
    Pecot J, Maillet L, Le Pen J, Vuillier C, Trecesson SC, Fetiveau A, Sarosiek KA, Bock FJ, Braun F, Letai A, Tait SW, Gautier F, Juin PP. Tight sequestration of BH3 proteins by BCL-xL at subcellular membranes contributes to apoptotic resistance. Cell Rep. 2016;17:3347–58.CrossRefPubMedGoogle Scholar
  84. 84.
    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;115:3304–13.CrossRefPubMedPubMedCentralGoogle Scholar
  85. 85.
    Mazumder S, Choudhary GS, Al-Harbi S, Almasan A. Mcl-1 Phosphorylation defines ABT-737 resistance that can be overcome by increased NOXA expression in leukemic B cells. Cancer Res. 2012;72:3069–79.CrossRefPubMedPubMedCentralGoogle Scholar
  86. 86.
    Roberts AW, Seymour JF, Brown JR, Wierda WG, Kipps TJ, Khaw SL, Carney DA, He SZ, Huang DC, Xiong H, Cui Y, Busman TA, McKeegan EM, Krivoshik AP, Enschede SH, Humerickhouse R. 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;30:488–96.CrossRefPubMedGoogle Scholar
  87. 87.
    Mason KD, Carpinelli MR, Fletcher JI, Collinge JE, Hilton AA, Ellis S, Kelly PN, Ekert PG, Metcalf D, Roberts AW, Huang DC, Kile BT. Programmed anuclear cell death delimits platelet life span. Cell. 2007;128:1173–86.CrossRefPubMedGoogle Scholar
  88. 88.
    Rudin CM, Hann CL, Garon EB, Ribeiro de Oliveira M, Bonomi PD, Camidge DR, Chu Q, Giaccone G, Khaira D, Ramalingam SS, Ranson MR, Dive C, McKeegan EM, Chyla BJ, Dowell BL, Chakravartty A, Nolan CE, Rudersdorf N, Busman TA, Mabry MH, Krivoshik AP, Humerickhouse RA, Shapiro GI, Gandhi L. Phase II study of single-agent navitoclax (ABT-263) and biomarker correlates in patients with relapsed small cell lung cancer. Clin Cancer Res. 2012;18:3163–9.CrossRefPubMedPubMedCentralGoogle Scholar
  89. 89.
    Gandhi L, Camidge DR, Ribeiro de Oliveira M, Bonomi P, Gandara D, Khaira D, Hann CL, McKeegan EM, Litvinovich E, Hemken PM, Dive C, Enschede SH, Nolan C, Chiu YL, Busman T, Xiong H, Krivoshik AP, Humerickhouse R, Shapiro GI, Rudin CM. 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;29:909–16.CrossRefPubMedPubMedCentralGoogle Scholar
  90. 90.
    Souers AJ, Leverson JD, Boghaert ER, Ackler SL, Catron ND, Chen J, Dayton BD, Ding H, Enschede SH, Fairbrother WJ, Huang DC, Hymowitz SG, Jin S, Khaw SL, Kovar PJ, Lam LT, Lee J, Maecker HL, Marsh KC, Mason KD, Mitten MJ, Nimmer PM, Oleksijew A, Park CH, Park CM, Phillips DC, Roberts AW, Sampath D, Seymour JF, Smith ML, Sullivan GM, Tahir SK, Tse C, Wendt MD, Xiao Y, Xue JC, Zhang H, Humerickhouse RA, Rosenberg SH, Elmore SW. ABT-199, a potent and selective BCL-2 inhibitor, achieves antitumor activity while sparing platelets. Nat Med. 2013;19:202–8.CrossRefPubMedGoogle Scholar
  91. 91.
    Pan R, Hogdal LJ, Benito JM, Bucci D, Han L, Borthakur G, Cortes JE, Deangelo DJ, Debose L, Mu H, Dohner H, Gaidzik V, Galinsky I, Golfman LS, Haferlach T, Harutyunyan KG, Hu J, Leverson JD, Marcucci G, Muschen M, Newman R, Park E, Ruvolo P, Ruvolo V, Ryan J, Schindela S, Zweidler-McKay PA, Stone RM, Kantarjian H, Andreeff M, Konopleva M, Letai A. Selective BCL-2 inhibition by ABT-199 causes on target cell death in acute myeloid leukemia. Cancer Discov. 2013;4(3):362–75.CrossRefPubMedPubMedCentralGoogle Scholar
  92. 92.
    Fischer U, Forster M, Rinaldi A, Risch T, Sungalee S, Warnatz HJ, Bornhauser B, Gombert M, Kratsch C, Stutz AM, Sultan M, Tchinda J, Worth CL, Amstislavskiy V, Badarinarayan N, Baruchel A, Bartram T, Basso G, Canpolat C, Cario G, Cave H, Dakaj D, Delorenzi M, Dobay MP, Eckert C, Ellinghaus E, Eugster S, Frismantas V, Ginzel S, Haas OA, Heidenreich O, Hemmrich-Stanisak G, Hezaveh K, Holl JI, Hornhardt S, Husemann P, Kachroo P, Kratz CP, Kronnie GT, Marovca B, Niggli F, McHardy AC, Moorman AV, Panzer-Grumayer R, Petersen BS, Raeder B, Ralser M, Rosenstiel P, Schafer D, Schrappe M, Schreiber S, Schutte M, Stade B, Thiele R, Weid N, Vora A, Zaliova M, Zhang L, Zichner T, Zimmermann M, Lehrach H, Borkhardt A, Bourquin JP, Franke A, Korbel JO, Stanulla M, Yaspo ML. Genomics and drug profiling of fatal TCF3-HLF-positive acute lymphoblastic leukemia identifies recurrent mutation patterns and therapeutic options. Nat Genet. 2015;47:1020–9.CrossRefPubMedPubMedCentralGoogle Scholar
  93. 93.
    Montero J, Stephansky J, Cai T, Griffin GK, Cabal-Hierro L, Togami K, Hogdal LJ, Galinsky I, Morgan EA, Aster JC, Davids MS, LeBoeuf NR, Stone RM, Konopleva M, Pemmaraju N, Letai A, Lane AA. Blastic plasmacytoid dendritic cell neoplasm is dependent on BCL-2 and sensitive to venetoclax. Cancer Discov. 2017;7(2):156–64.CrossRefPubMedGoogle Scholar
  94. 94.
    Bate-Eya LT, den Hartog IJ, van der Ploeg I, Schild L, Koster J, Santo EE, Westerhout EM, Versteeg R, Caron HN, Molenaar JJ, Dolman ME. High efficacy of the BCL-2 inhibitor ABT199 (venetoclax) in BCL-2 high-expressing neuroblastoma cell lines and xenografts and rational for combination with MCL-1 inhibition. Oncotarget. 2016;7:27946–58.CrossRefPubMedPubMedCentralGoogle Scholar
  95. 95.
    Roberts AW, Davids MS, Pagel JM, Kahl BS, Puvvada SD, Gerecitano JF, Kipps TJ, Anderson MA, Brown JR, Gressick L, Wong S, Dunbar M, Zhu M, Desai MB, Cerri E, Heitner Enschede S, Humerickhouse RA, Wierda WG, Seymour JF. Targeting BCL2 with venetoclax in relapsed chronic lymphocytic leukemia. N Engl J Med. 2016;374:311–22.CrossRefPubMedGoogle Scholar
  96. 96.
    Stilgenbauer S, Eichhorst B, Schetelig J, Coutre S, Seymour JF, Munir T, Puvvada SD, Wendtner CM, Roberts AW, Jurczak W, Mulligan SP, Bottcher S, Mobasher M, Zhu M, Desai M, Chyla B, Verdugo M, Enschede SH, Cerri E, Humerickhouse R, Gordon G, Hallek M, Wierda WG. Venetoclax in relapsed or refractory chronic lymphocytic leukaemia with 17p deletion: a multicentre, open-label, phase 2 study. Lancet Oncol. 2016;17:768–78.CrossRefPubMedGoogle Scholar
  97. 97.
    Anderson MA, Deng J, Seymour JF, Tam C, Kim SY, Fein J, Yu L, Brown JR, Westerman D, Si EG, Majewski IJ, Segal D, Heitner Enschede SL, Huang DC, Davids MS, Letai A, Roberts AW. The BCL2 selective inhibitor venetoclax induces rapid onset apoptosis of CLL cells in patients via a TP53-independent mechanism. Blood. 2016;127:3215–24.CrossRefPubMedPubMedCentralGoogle Scholar
  98. 98.
    Vogler M, Dinsdale D, Dyer MJ, Cohen GM. ABT-199 selectively inhibits BCL2 but not BCL2L1 and efficiently induces apoptosis of chronic lymphocytic leukaemic cells but not platelets. Br J Haematol. 2013;163:139–42.CrossRefPubMedGoogle Scholar
  99. 99.
    Davids MS, Roberts AW, Seymour JF, Pagel JM, Kahl BS, Wierda WG, Puvvada S, Kipps TJ, Anderson MA, Salem AH, Dunbar M, Zhu M, Peale F, Ross JA, Gressick L, Desai M, Kim SY, Verdugo M, Humerickhouse RA, Gordon GB, Gerecitano JF. Phase I first-in-human study of venetoclax in patients with relapsed or refractory non-hodgkin lymphoma. J Clin Oncol. 2017;35:826–33.CrossRefPubMedPubMedCentralGoogle Scholar
  100. 100.
    Wei G, Margolin AA, Haery L, Brown E, Cucolo L, Julian B, Shehata S, Kung AL, Beroukhim R, Golub TR. Chemical genomics identifies small-molecule MCL1 repressors and BCL-xL as a predictor of MCL1 dependency. Cancer Cell. 2012;21:547–62.CrossRefPubMedPubMedCentralGoogle Scholar
  101. 101.
    Faber AC, Coffee EM, Costa C, Dastur A, Ebi H, Hata AN, Yeo AT, Edelman EJ, Song Y, Tam AT, Boisvert JL, Milano RJ, Roper J, Kodack DP, Jain RK, Corcoran RB, Rivera MN, Ramaswamy S, Hung KE, Benes CH, Engelman JA. mTOR inhibition specifically sensitizes colorectal cancers with KRAS or BRAF mutations to BCL-2/BCL-XL inhibition by suppressing MCL-1. Cancer Discov. 2014;4:42–52.CrossRefPubMedGoogle Scholar
  102. 102.
    Park D, Magis AT, Li R, Owonikoko TK, Sica GL, Sun SY, Ramalingam SS, Khuri FR, Curran WJ, Deng X. Novel small-molecule inhibitors of Bcl-XL to treat lung cancer. Cancer Res. 2013;73:5485–96.CrossRefPubMedPubMedCentralGoogle Scholar
  103. 103.
    Leverson JD, Phillips DC, Mitten MJ, Boghaert ER, Diaz D, Tahir SK, Belmont LD, Nimmer P, Xiao Y, Ma XM, Lowes KN, Kovar P, Chen J, Jin S, Smith M, Xue J, Zhang H, Oleksijew A, Magoc TJ, Vaidya KS, Albert DH, Tarrant JM, La N, Wang L, Tao ZF, Wendt MD, Sampath D, Rosenberg SH, Tse C, Huang DC, Fairbrother WJ, Elmore SW, Souers AJ. Exploiting selective BCL-2 family inhibitors to dissect cell survival dependencies and define improved strategies for cancer therapy. Sci Transl Med. 2015;7:279ra240.CrossRefGoogle Scholar
  104. 104.
    Punnoose EA, Leverson JD, Peale F, Boghaert ER, Belmont LD, Tan N, Young A, Mitten M, Ingalla E, Darbonne WC, Oleksijew A, Tapang P, Yue P, Oeh J, Lee L, Maiga S, Fairbrother WJ, Amiot M, Souers AJ, Sampath D. Expression profile of BCL-2, BCL-XL, and MCL-1 predicts pharmacological response to the BCL-2 selective antagonist venetoclax in multiple myeloma models. Molecul Cancer Therap. 2016;15:1132–44.CrossRefGoogle Scholar
  105. 105.
    Choudhary GS, Al-Harbi S, Mazumder S, Hill BT, Smith MR, Bodo J, Hsi ED, Almasan A. MCL-1 and BCL-xL-dependent resistance to the BCL-2 inhibitor ABT-199 can be overcome by preventing PI3K/AKT/mTOR activation in lymphoid malignancies. Cell Death Dis. 2015;6:e1593.CrossRefPubMedPubMedCentralGoogle Scholar
  106. 106.
    Nikiforov MA, Riblett M, Tang WH, Gratchouck V, Zhuang D, Fernandez Y, Verhaegen M, Varambally S, Chinnaiyan AM, Jakubowiak AJ, Soengas MS. Tumor cell-selective regulation of NOXA by c-MYC in response to proteasome inhibition. Proc Natl Acad Sci U S A. 2007;104:19488–93.CrossRefPubMedPubMedCentralGoogle Scholar
  107. 107.
    Chan SM, Thomas D, Corces-Zimmerman MR, Xavy S, Rastogi S, Hong WJ, Zhao F, Medeiros BC, Tyvoll DA, Majeti R. Isocitrate dehydrogenase 1 and 2 mutations induce BCL-2 dependence in acute myeloid leukemia. Nat Med. 2015;21:178–84.CrossRefPubMedPubMedCentralGoogle Scholar
  108. 108.
    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;123:4111–9.CrossRefPubMedGoogle Scholar
  109. 109.
    Tang H, Shao H, Yu C, Hou J. Mcl-1 downregulation by YM155 contributes to its synergistic anti-tumor activities with ABT-263. Biochem Pharmacol. 2011;82:1066–72.CrossRefPubMedGoogle Scholar
  110. 110.
    Tahir SK, Wass J, Joseph MK, Devanarayan V, Hessler P, Zhang H, Elmore SW, Kroeger PE, Tse C, Rosenberg SH, Anderson MG. Identification of expression signatures predictive of sensitivity to the Bcl-2 family member inhibitor ABT-263 in small cell lung carcinoma and leukemia/lymphoma cell lines. Molecul Cancer Therapeut. 2010;9:545–57.CrossRefGoogle Scholar
  111. 111.
    Shi J, Zhou Y, Huang HC, Mitchison TJ. Navitoclax (ABT-263) accelerates apoptosis during drug-induced mitotic arrest by antagonizing Bcl-xL. Cancer Res. 2011;71:4518–26.CrossRefPubMedPubMedCentralGoogle Scholar
  112. 112.
    Rahmani M, Aust MM, Hawkins E, Parker RE, Ross M, Kmieciak M, Reshko LB, Rizzo KA, Dumur CI, Ferreira-Gonzalez A, Grant S. 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;100:1553–63.CrossRefPubMedPubMedCentralGoogle Scholar
  113. 113.
    Chen S, Dai Y, Harada H, Dent P, Grant S. Mcl-1 down-regulation potentiates ABT-737 lethality by cooperatively inducing Bak activation and Bax translocation. Cancer Res. 2007;67:782–91.CrossRefPubMedGoogle Scholar
  114. 114.
    Klanova M, Andera L, Brazina J, Svadlenka J, Benesova S, Soukup J, Prukova D, Vejmelkova D, Jaksa R, Helman K, Vockova P, Lateckova L, Molinsky J, Maswabi BC, Alam M, Kodet R, Pytlik R, Trneny M, Klener P. Targeting of BCL2 Family Proteins with ABT-199 and Homoharringtonine Reveals BCL2- and MCL1-Dependent Subgroups of Diffuse Large B-Cell Lymphoma. Clin Cancer Res. 2016;22:1138–49.CrossRefPubMedGoogle Scholar
  115. 115.
    Bojarczuk K, Sasi BK, Gobessi S, Innocenti I, Pozzato G, Laurenti L, Efremov DG. BCR signaling inhibitors differ in their ability to overcome Mcl-1-mediated resistance of CLL B cells to ABT-199. Blood. 2016;127:3192–201.CrossRefPubMedGoogle Scholar
  116. 116.
    Zhang H, Guttikonda S, Roberts L, Uziel T, Semizarov D, Elmore SW, Leverson JD, Lam LT. Mcl-1 is critical for survival in a subgroup of non-small-cell lung cancer cell lines. Oncogene. 2011;30:1963–8.CrossRefPubMedGoogle Scholar
  117. 117.
    Senft D, Berking C, Graf SA, Kammerbauer C, Ruzicka T, Besch R. Selective induction of cell death in melanoma cell lines through targeting of Mcl-1 and A1. PLoS One. 2012;7:e30821.CrossRefPubMedPubMedCentralGoogle Scholar
  118. 118.
    Morales AA, Kurtoglu M, Matulis SM, Liu J, Siefker D, Gutman DM, Kaufman JL, Lee KP, Lonial S, Boise LH. Distribution of Bim determines Mcl-1 dependence or codependence with Bcl-xL/Bcl-2 in Mcl-1-expressing myeloma cells. Blood. 2011;118:1329–39.CrossRefPubMedPubMedCentralGoogle Scholar
  119. 119.
    Aichberger KJ, Mayerhofer M, Krauth MT, Skvara H, Florian S, Sonneck K, Akgul C, Derdak S, Pickl WF, Wacheck V, Selzer E, Monia BP, Moriggl R, Valent P, Sillaber C. 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;105:3303–11.CrossRefPubMedGoogle Scholar
  120. 120.
    Leverson JD, Zhang H, Chen J, Tahir SK, Phillips DC, Xue J, Nimmer P, Jin S, Smith M, Xiao Y, Kovar P, Tanaka A, Bruncko M, Sheppard GS, Wang L, Gierke S, Kategaya L, Anderson DJ, Wong C, Eastham-Anderson J, Ludlam MJ, Sampath D, Fairbrother WJ, Wertz I, Rosenberg SH, Tse C, Elmore SW, Souers AJ. 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.CrossRefPubMedPubMedCentralGoogle Scholar
  121. 121.
    Soderquist R S, Eastman A. BCL2 inhibitors as anticancer drugs: a plethora of misleading BH3 mimetics. Molecul Cancer Therapeut. 2016;15:2011–7.CrossRefGoogle Scholar
  122. 122.
    Xiao Y, Nimmer P, Sheppard GS, Bruncko M, Hessler P, Lu X, Roberts-Rapp L, Pappano WN, Elmore SW, Souers AJ, Leverson JD, Phillips DC. MCL-1 is a key determinant of breast cancer cell survival: validation of MCL-1 dependency utilizing a highly selective small molecule inhibitor. Molecul Cancer Therapeut. 2015;14:1837–47.CrossRefGoogle Scholar
  123. 123.
    Kotschy A, Szlavik Z, Murray J, Davidson J, Maragno AL, Le Toumelin-Braizat G, Chanrion M, Kelly GL, Gong JN, Moujalled DM, Bruno A, Csekei M, Paczal A, Szabo ZB, Sipos S, Radics G, Proszenyak A, Balint B, Ondi L, Blasko G, Robertson A, Surgenor A, Dokurno P, Chen I, Matassova N, Smith J, Pedder C, Graham C, Studeny A, Lysiak-Auvity G, Girard AM, Grave F, Segal D, Riffkin CD, Pomilio G, Galbraith LC, Aubrey BJ, Brennan MS, Herold MJ, Chang C, Guasconi G, Cauquil N, Melchiore F, Guigal-Stephan N, Lockhart B, Colland F, Hickman JA, Roberts AW, Huang DC, Wei AH, Strasser A, Lessene G, Geneste O. The MCL1 inhibitor S63845 is tolerable and effective in diverse cancer models. Nature. 2016;538:477–82.CrossRefPubMedGoogle Scholar
  124. 124.
    Perciavalle RM, Opferman JT. Delving deeper: MCL-1’s contributions to normal and cancer biology. Trends Cell Biol. 2013;23:22–9.CrossRefPubMedGoogle Scholar
  125. 125.
    Opferman JT, Letai A, Beard C, Sorcinelli MD, Ong CC, Korsmeyer SJ. Development and maintenance of B and T lymphocytes requires antiapoptotic MCL-1. Nature. 2003;426:671–6.CrossRefPubMedGoogle Scholar
  126. 126.
    Dzhagalov I, St John A, He YW. The antiapoptotic protein Mcl-1 is essential for the survival of neutrophils but not macrophages. Blood. 2007;109:1620–6.CrossRefPubMedPubMedCentralGoogle Scholar
  127. 127.
    Arbour N, Vanderluit JL, Le Grand JN, Jahani-Asl A, Ruzhynsky VA, Cheung EC, Kelly MA, MacKenzie AE, Park DS, Opferman JT, Slack RS. Mcl-1 is a key regulator of apoptosis during CNS development and after DNA damage. J Neurosci. 2008;28:6068–78.CrossRefPubMedPubMedCentralGoogle Scholar
  128. 128.
    Parikh SA, Kantarjian H, Schimmer A, Walsh W, Asatiani E, El-Shami K, Winton E, Verstovsek S. Phase II study of obatoclax mesylate (GX15-070), a small-molecule BCL-2 family antagonist, for patients with myelofibrosis. Clin Lymphoma Myeloma Leuk. 2010;10:285–9.CrossRefPubMedGoogle Scholar
  129. 129.
    Mills JR, Hippo Y, Robert F, Chen SM, Malina A, Lin CJ, Trojahn U, Wendel HG, Charest A, Bronson RT, Kogan SC, Nadon R, Housman DE, Lowe SW, Pelletier J. mTORC1 promotes survival through translational control of Mcl-1. Proc Natl Acad Sci U S A. 2008;105:10853–8.CrossRefPubMedPubMedCentralGoogle Scholar
  130. 130.
    Schatz JH, Oricchio E, Wolfe AL, Jiang M, Linkov I, Maragulia J, Shi W, Zhang Z, Rajasekhar VK, Pagano NC, Porco JA Jr, Teruya-Feldstein J, Rosen N, Zelenetz AD, Pelletier J, Wendel HG. Targeting cap-dependent translation blocks converging survival signals by AKT and PIM kinases in lymphoma. J Exp Med. 2011;208:1799–807.CrossRefPubMedPubMedCentralGoogle Scholar
  131. 131.
    Gregory GP, Hogg SJ, Kats LM, Vidacs E, Baker AJ, Gilan O, Lefebure M, Martin BP, Dawson MA, Johnstone RW, Shortt J. CDK9 inhibition by dinaciclib potently suppresses Mcl-1 to induce durable apoptotic responses in aggressive MYC-driven B-cell lymphoma in vivo. Leukemia. 2015;29:1437–41.CrossRefPubMedPubMedCentralGoogle Scholar
  132. 132.
    Alsayegh K, Matsuura K, Sekine H, Shimizu T. Dinaciclib potently suppresses MCL-1 and selectively induces the cell death in human iPS cells without affecting the viability of cardiac tissue. Sci Rep. 2017;7:45577.CrossRefPubMedPubMedCentralGoogle Scholar
  133. 133.
    MacCallum DE, Melville J, Frame S, Watt K, Anderson S, Gianella-Borradori A, Lane DP, Green SR. Seliciclib (CYC202, R-Roscovitine) induces cell death in multiple myeloma cells by inhibition of RNA polymerase II-dependent transcription and down-regulation of Mcl-1. Cancer Res. 2005;65:5399–407.CrossRefPubMedGoogle Scholar
  134. 134.
    Mitchell C, Yacoub A, Hossein H, Martin AP, Bareford MD, Eulitt P, Yang C, Nephew KP, Dent P. Inhibition of MCL-1 in breast cancer cells promotes cell death in vitro and in vivo. Cancer Biol Therapy. 2010;10:903–17.CrossRefGoogle Scholar
  135. 135.
    Xu H, Krystal GW. Actinomycin D decreases Mcl-1 expression and acts synergistically with ABT-737 against small cell lung cancer cell lines. Clin Cancer Res. 2010;16:4392–400.CrossRefPubMedGoogle Scholar
  136. 136.
    Rapino F, Naumann I, Fulda S. Bortezomib antagonizes microtubule-interfering drug-induced apoptosis by inhibiting G2/M transition and MCL-1 degradation. Cell Death Dis. 2013;4:e925.CrossRefPubMedPubMedCentralGoogle Scholar
  137. 137.
    Li L, Pongtornpipat P, Tiutan T, Kendrick SL, Park S, Persky DO, Rimsza LM, Puvvada SD, Schatz JH. Synergistic induction of apoptosis in high-risk DLBCL by BCL2 inhibition with ABT-199 combined with pharmacologic loss of MCL1. Leukemia. 2015;29:1702–12.CrossRefPubMedPubMedCentralGoogle Scholar
  138. 138.
    Gojo I, Sadowska M, Walker A, Feldman EJ, Iyer SP, Baer MR, Sausville EA, Lapidus RG, Zhang D, Zhu Y, Jou YM, Poon J, Small K, Bannerji R. Clinical and laboratory studies of the novel cyclin-dependent kinase inhibitor dinaciclib (SCH 727965) in acute leukemias. Cancer Chemother Pharmacol. 2013;72:897–908.CrossRefPubMedPubMedCentralGoogle Scholar
  139. 139.
    Baker A, Gregory GP, Verbrugge I, Kats L, Hilton JJ, Vidacs E, Lee EM, Lock RB, Zuber J, Shortt J, Johnstone RW. The CDK9 inhibitor dinaciclib exerts potent apoptotic and antitumor effects in preclinical models of MLL-rearranged acute myeloid leukemia. Cancer Res. 2016;76:1158–69.CrossRefPubMedGoogle Scholar
  140. 140.
    Wiggins CM, Tsvetkov P, Johnson M, Joyce CL, Lamb CA, Bryant NJ, Komander D, Shaul Y, Cook SJ. BIM(EL), an intrinsically disordered protein, is degraded by 20S proteasomes in the absence of poly-ubiquitylation. J Cell Sci. 2011;124:969–77.CrossRefPubMedGoogle Scholar
  141. 141.
    Serasinghe MN, Missert DJ, Asciolla JJ, Podgrabinska S, Wieder SY, Izadmehr S, Belbin G, Skobe M, Chipuk JE. Anti-apoptotic BCL-2 proteins govern cellular outcome following B-RAF inhibition and can be targeted to reduce resistance. Oncogene. 2014;34(7):857–67.CrossRefPubMedPubMedCentralGoogle Scholar
  142. 142.
    Frederick DT, Salas Fragomeni RA, Schalck A, Ferreiro-Neira I, Hoff T, Cooper ZA, Haq R, Panka DJ, Kwong LN, Davies MA, Cusack JC, Flaherty KT, Fisher DE, Mier JW, Wargo JA, Sullivan RJ. Clinical profiling of BCL-2 family members in the setting of BRAF inhibition offers a rationale for targeting de novo resistance using BH3 mimetics. PLoS One. 2014;9:e101286.CrossRefPubMedPubMedCentralGoogle Scholar
  143. 143.
    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;4:1681–9; discussion 1690.CrossRefPubMedGoogle Scholar
  144. 144.
    Deng J, Shimamura T, Perera S, Carlson NE, Cai D, Shapiro GI, Wong KK, Letai A. Proapoptotic BH3-only BCL-2 family protein BIM connects death signaling from epidermal growth factor receptor inhibition to the mitochondrion. Cancer Res. 2007;67:11867–75.CrossRefPubMedGoogle Scholar
  145. 145.
    Tan N, Wong M, Nannini MA, Hong R, Lee LB, Price S, Williams K, Savy PP, Yue P, Sampath D, Settleman J, Fairbrother WJ, Belmont LD. Bcl-2/Bcl-xL inhibition increases the efficacy of MEK inhibition alone and in combination with PI3 kinase inhibition in lung and pancreatic tumor models. Molecul Cancer Therapeut. 2013;12:853–64.CrossRefGoogle Scholar
  146. 146.
    Wali VB, Langdon CG, Held MA, Platt JT, Patwardhan GA, Safonov A, Aktas B, Pusztai L, Stern DF, Hatzis C. Systematic drug screening identifies tractable targeted combination therapies in triple-negative breast cancer. Cancer Res. 2017;77:566–78.CrossRefPubMedGoogle Scholar
  147. 147.
    Zheng L, Yang W, Zhang C, Ding WJ, Zhu H, Lin NM, Wu HH, He QJ, Yang B. GDC-0941 sensitizes breast cancer to ABT-737 in vitro and in vivo through promoting the degradation of Mcl-1. Cancer Lett. 2011;309:27–36.CrossRefPubMedGoogle Scholar
  148. 148.
    Seymour JF, Ma S, Brander DM, Choi MY, Barrientos J, Davids MS, Anderson MA, Beaven AW, Rosen ST, Tam CS, Prine B, Agarwal SK, Munasinghe W, Zhu M, Lash LL, Desai M, Cerri E, Verdugo M, Kim SY, Humerickhouse RA, Gordon GB, Kipps TJ, Roberts AW. Venetoclax plus rituximab in relapsed or refractory chronic lymphocytic leukaemia: a phase 1b study. Lancet Oncol. 2017;18:230–40.CrossRefPubMedPubMedCentralGoogle Scholar
  149. 149.
    Nakagawa T, Takeuchi S, Yamada T, Ebi H, Sano T, Nanjo S, Ishikawa D, Sato M, Hasegawa Y, Sekido Y, Yano S. EGFR-TKI resistance due to BIM polymorphism can be circumvented in combination with HDAC inhibition. Cancer Res. 2013;73:2428–34.CrossRefPubMedGoogle Scholar
  150. 150.
    Tanimoto A, Takeuchi S, Arai S, Fukuda K, Yamada T, Roca X, Ong ST, Yano S. Histone deacetylase 3 inhibition overcomes BIM deletion polymorphism-mediated osimertinib-resistance in EGFR-mutant lung cancer. Clin Cancer Res. 2017;23(12):3139–49.CrossRefPubMedGoogle Scholar
  151. 151.
    Hsieh AC, Costa M, Zollo O, Davis C, Feldman ME, Testa JR, Meyuhas O, Shokat KM, Ruggero D. Genetic dissection of the oncogenic mTOR pathway reveals druggable addiction to translational control via 4EBP-eIF4E. Cancer Cell. 2010;17:249–61.CrossRefPubMedPubMedCentralGoogle Scholar
  152. 152.
    Cope CL, Gilley R, Balmanno K, Sale MJ, Howarth KD, Hampson M, Smith PD, Guichard SM, Cook SJ. Adaptation to mTOR kinase inhibitors by amplification of eIF4E to maintain cap-dependent translation. J Cell Sci. 2014;127:788–800.CrossRefPubMedGoogle Scholar
  153. 153.
    Phillips DC, Xiao Y, Lam LT, Litvinovich E, Roberts-Rapp L, Souers AJ, Leverson JD. Loss in MCL-1 function sensitizes non-Hodgkin’s lymphoma cell lines to the BCL-2-selective inhibitor venetoclax (ABT-199). Blood Cancer J. 2015;5:e368.Google Scholar
  154. 154.
    Dangi-Garimella S. FDA grants accelerated approval for ibrutinib for CLL. Am J Manag Care. 2014;20:E10.PubMedGoogle Scholar
  155. 155.
    Cervantes-Gomez F, Lamothe B, Woyach JA, Wierda W, Keating MJ, Balakrishnan K, Gandhi V. Pharmacological and protein profiling suggest ABT-199 as optimal partner with ibrutinib in chronic lymphocytic leukemia. Clin Cancer Res. 2015;21(16):3705–15.CrossRefPubMedPubMedCentralGoogle Scholar
  156. 156.
    Fischer K, Al-Sawaf O, Fink AM, Dixon M, Bahlo J, Warburton S, Kipps TJ, Weinkove R, Robinson S, Seiler T, Opat S, Owen C, Lopez J, Humphrey K, Humerickhouse R, Tausch E, Frenzel L, Eichhorst B, Wendtner CM, Stilgenbauer S, Langerak AW, van Dongen JJ, Boettcher S, Ritgen M, Goede V, Mobasher M, Hallek M. Venetoclax and obinutuzumab in chronic lymphocytic leukemia. Blood. 2017;129:2702–05.CrossRefPubMedPubMedCentralGoogle Scholar
  157. 157.
    Kuo HP, Ezell SA, Schweighofer KJ, Cheung LW, Hsieh S, Apatira M, Sirisawad M, Eckert K, Hsu SJ, Chen CT, Beaupre DM, Versele M, Chang BY. Combination of ibrutinib and ABT-199 in diffuse large B-cell lymphoma and follicular lymphoma. Mol Cancer Ther. 2017;16(7):1246–56.Google Scholar
  158. 158.
    Zelenetz AD, Salles GA, Mason KD, Casulo C, Le Gouill S, Sehn LH, Tilly H, Cartron G, Chamuleau MED, Goy A, Tam C, Lugtenburg PJ, Elstrom RL, Hsu W, Mobasher M, Morschhauser F. Phase 1b study of venetoclax plus R- or G-CHOP in patients with B-cell non-Hodgkin lymphoma. J Clin Oncol. 2016;34:suppl.7566.Google Scholar
  159. 159.
    De Vos S, Swinnen L, Kozloff M, Wang D, Reid E, Nastoupil L, Fowler N, Cordero J, D’Amico D, Diehl S, Dunbar M, Zhu M, Wong S, Enschede SH, Chien D, Humerickhouse RA, Flowers C. A dose-escalation study of venetoclax (ABT-199/GDC-0199) in combination with bendamustine and rituximab in patients with relapsed or refractory Non-Hodgkin’s lymphoma. Blood. 2015;126:255.Google Scholar
  160. 160.
    Zinzani PL, Topp MS, Yuen SL, Rusconi C, Fleury I, Pro B, Gritti G, Crump M, Hsu W, Punnoose EA, Hilger J, Mobasher M, Hiddermann W. Phase 2 study of venetoclax plus rituximab or randomized ven plus bendamustine + rituximab (BR) versus BR in patients with relapsed/refractory follicular lymphoma: interim data. Blood. 2016;128:617.Google Scholar
  161. 161.
    DiNardo C, Pollyea D, Pratz K, Thirman MJ, Letai A, Frattini M, Jonas B, Leverson J, Zhu M, Dunbar M, Falotico N, Kirby R, Agarwal S, Mabry M, Potluri J, Humerickhouse RA, Kantarjian HM, Konopleva M. A phase 1b study of venetoclax (ABT-199/GDC-0199) in combination with decitabine or azacitidine in treatment-naïve patients with acute myelogenous leukemia who are to 65 years and not eligible for standard induction therapy. Blood. 2015;126:327.Google Scholar
  162. 162.
    Wei A, Strickland SA, Roboz GJ, Hou J-Z, Fiedler W, Lin TL, Martinelli G, Walter RB, Enjeti A, Fakouhi K, Darden DE, Dunbar M, Zhu M, Agarwal S, Salem AH, Mabry M, Hayslip J. Safety and efficacy of venetoclax plus low-dose cytarabine in treatment-naïve patients aged 65 years with acute myeloid leukemia. Blood. 2016;128:102.Google Scholar
  163. 163.
    Tam CSL, Roberts AW, Anderson MA, Dawson S-J, Hicks RJ. Burbury K, Turner G, Di Iulio J, Bressel M, Westerman DA, Agarwal R, Pott C, Dreyling MH, Dawson MA, Seymour JF. Combination ibrutinib (Ibr) and venetoclax (Ven) for the treatment of mantle cell lymphoma (MCL): Primary endpoint assessment of the phase 2 AIM study. J Clin Oncol. 2017;35:suppl.7520.Google Scholar
  164. 164.
    Kumar S, Vij R, Kaufman JL, Mikhael J, Facon T, Pegourie B, Benboubker L, Gasparetto C, Amiot M, Moreau P, Diehl S, Alzate S, Ross JA, Dunbar M, Zhu M, Agarwal SK, Leverson J, Maciag PC, Verdugo ME, Touzeau C. Phase I venetoclax monotherapy for relapsed/refractory multiple myeloma. J Clin Oncol. 2016;34:suppl.8032.Google Scholar
  165. 165.
    Kipps TJ, Eradat H, Grosicki S, Catalano J, Cosolo W, Dyagil IS, Yalamanchili S, Chai A, Sahasranaman S, Punnoose E, Hurst D, Pylypenko H. 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.Google Scholar
  166. 166.
    Cleary JM, Lima CM, Hurwitz HI, Montero AJ, Franklin C, Yang J, Graham A, Busman T, Mabry M, Holen K, Shapiro GI, Uronis H. 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;32:937–45.Google Scholar
  167. 167.
    Tolcher AW, LoRusso P, Arzt J, Busman TA, Lian G, Rudersdorf NS, Vanderwal CA, Kirschbrown W, Holen KD, Rosen LS. Safety, efficacy, and pharmacokinetics of navitoclax (ABT-263) in combination with erlotinib in patients with advanced solid tumors. Cancer Chemother Pharmacol. 2015;76:1025–32.CrossRefPubMedGoogle Scholar
  168. 168.
    Lochmann TL, Floros KV, Naseri M, Powell KM, Cook W, March RJ, Stein GT, Greninger P, Kato Maves Y, Saunders LR, Dylla SJ, Costa C, Boikos SA, Leverson JD, Souers AJ, Krystal GW, Harada H, Benes CH, Faber AC. Venetoclax is effective in small cell lung cancers with high BCL-2 expression. Clin Cancer Res. 2017.  https://doi.org/10.1158/1078-0432.CCR-17-1606.

Copyright information

© Springer International Publishing AG, part of Springer Nature 2018

Authors and Affiliations

  • Konstantinos V. Floros
    • 1
  • Anthony C. Faber
    • 1
  • Hisashi Harada
    • 1
  1. 1.Philips Institute for Oral Health Research, VCU School of Dentistry and Massey Cancer CenterVirginia Commonwealth UniversityRichmondUSA

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