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Targeting Apoptosis in Cancer

  • Evolving Therapies (RM Bukowski, Section Editor)
  • Published:
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Abstract

Purpose of Review

Apoptosis is a major mechanism of cancer cell death. Thus, evasion of apoptosis results in therapy resistance. Here, we review apoptosis modulators in cancer and their recent developments, including MDM2 inhibitors and kinase inhibitors that can induce effective apoptosis.

Recent Findings

Both extrinsic pathways (external stimuli through cell surface death receptor) and intrinsic pathways (mitochondrial-mediated regulation upon genotoxic stress) regulate the complex process of apoptosis through orchestration of various proteins such as members of the BCL-2 family. Dysregulation within these complex steps can result in evasion of apoptosis. However, via the combined evolution of medicinal chemistry and molecular biology, omics assays have led to innovative inducers of apoptosis and inhibitors of anti-apoptotic regulators. Many of these agents are now being tested in cancer patients in early-phase trials.

Summary

We believe that despite a sluggish speed of development, apoptosis targeting holds promise as a relevant strategy in cancer therapeutics.

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Data Availability

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References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. Sheridan JP, Marsters SA, Pitti RM, Gurney A, Skubatch M, Baldwin D, et al. Control of TRAIL-induced apoptosis by a family of signaling and decoy receptors. Science (New York, NY). 1997;277(5327):818–21.

    Article  CAS  Google Scholar 

  2. Marsters SA, Pitti RA, Sheridan JP, Ashkenazi A. Control of apoptosis signaling by Apo2 ligand. Recent Prog Horm Res. 1999;54:225–34.

    CAS  PubMed  Google Scholar 

  3. Reed JC. Dysregulation of apoptosis in cancer. J Clin Oncol: official journal of the American Society of Clinical Oncology. 1999;17(9):2941–53.

    Article  CAS  Google Scholar 

  4. Kapur A, Felder M, Fass L, Kaur J, Czarnecki A, Rathi K, et al. Modulation of oxidative stress and subsequent induction of apoptosis and endoplasmic reticulum stress allows citral to decrease cancer cell proliferation. Sci Rep. 2016;6:27530.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Larsen BD, Sorensen CS. The caspase-activated DNase: apoptosis and beyond. FEBS J. 2017;284(8):1160–70.

    Article  CAS  PubMed  Google Scholar 

  6. Criscitiello C, Azim HA Jr, Schouten PC, Linn SC, Sotiriou C. Understanding the biology of triple-negative breast cancer. Ann Oncol. 2012;23(Suppl 6):vi13-8.

    Article  PubMed  Google Scholar 

  7. Reis-Filho JS, Tutt AN. Triple negative tumours: a critical review. Histopathology. 2008;52(1):108–18.

    Article  CAS  PubMed  Google Scholar 

  8. Carey L, Winer E, Viale G, Cameron D, Gianni L. Triple-negative breast cancer: disease entity or title of convenience? Nat Rev Clin Oncol. 2010;7(12):683–92.

    Article  PubMed  Google Scholar 

  9. King KL, Cidlowski JA. Cell cycle regulation and apoptosis. Annu Rev Physiol. 1998;60:601–17.

    Article  CAS  PubMed  Google Scholar 

  10. Lovric MM, Hawkins CJ. TRAIL treatment provokes mutations in surviving cells. Oncogene. 2010;29(36):5048–60.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Stadel D, Mohr A, Ref C, MacFarlane M, Zhou S, Humphreys R, et al. TRAIL-induced apoptosis is preferentially mediated via TRAIL receptor 1 in pancreatic carcinoma cells and profoundly enhanced by XIAP inhibitors. Clin Cancer Res. 2010;16(23):5734–49.

    Article  CAS  PubMed  Google Scholar 

  12. Choe SC, Hamacher-Brady A, Brady NR. Autophagy capacity and sub-mitochondrial heterogeneity shape Bnip3-induced mitophagy regulation of apoptosis. Cell Commun Signal. 2015;13:37.

    Article  PubMed  PubMed Central  Google Scholar 

  13. Wolff S, Erster S, Palacios G, Moll UM. p53’s mitochondrial translocation and MOMP action is independent of Puma and Bax and severely disrupts mitochondrial membrane integrity. Cell Res. 2008;18(7):733–44.

    Article  CAS  PubMed  Google Scholar 

  14. Ramakrishnan V, Gomez M, Prasad V, Kimlinger T, Painuly U, Mukhopadhyay B, et al. Smac mimetic LCL161 overcomes protective ER stress induced by obatoclax, synergistically causing cell death in multiple myeloma. Oncotarget. 2016;7(35):56253–65.

    Article  PubMed  PubMed Central  Google Scholar 

  15. Iurlaro R, Munoz-Pinedo C. Cell death induced by endoplasmic reticulum stress. FEBS J. 2016;283(14):2640–52.

    Article  CAS  PubMed  Google Scholar 

  16. Du C, Fang M, Li Y, Li L, Wang X. Smac, a mitochondrial protein that promotes cytochrome c-dependent caspase activation by eliminating IAP inhibition. Cell. 2000;102(1):33–42.

    Article  CAS  PubMed  Google Scholar 

  17. Pierceall WE, Kornblau SM, Carlson NE, Huang X, Blake N, Lena R, et al. BH3 profiling discriminates response to cytarabine-based treatment of acute myelogenous leukemia. Mol Cancer Ther. 2013;12(12):2940–9.

    Article  CAS  PubMed  Google Scholar 

  18. Zhang Z, Yang H, Wu G, Li Z, Song T, Li XQ. Probing the difference between BH3 groove of Mcl-1 and Bcl-2 protein: implications for dual inhibitors design. Eur J Med Chem. 2011;46(9):3909–16.

    Article  CAS  PubMed  Google Scholar 

  19. Scaffidi C, Fulda S, Srinivasan A, Friesen C, Li F, Tomaselli KJ, et al. Two CD95 (APO-1/Fas) signaling pathways. EMBO J. 1998;17(6):1675–87.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Ozoren N, El-Deiry WS. Defining characteristics of types I and II apoptotic cells in response to TRAIL. Neoplasia (New York, NY). 2002;4(6):551–7.

    Article  Google Scholar 

  21. Roy S, Nicholson DW. Cross-talk in cell death signaling. J Exp Med. 2000;192(8):21–6.

    Article  CAS  PubMed  Google Scholar 

  22. Sessler T, Healy S, Samali A, Szegezdi E. Structural determinants of DISC function: new insights into death receptor-mediated apoptosis signalling. Pharmacol Ther. 2013;140(2):186–99.

    Article  CAS  PubMed  Google Scholar 

  23. Wiley SR, Schooley K, Smolak PJ, Din WS, Huang CP, Nicholl JK, et al. Identification and characterization of a new member of the TNF family that induces apoptosis. Immunity. 1995;3(6):673–82.

    Article  CAS  PubMed  Google Scholar 

  24. Wang S, El-Deiry WS. TRAIL and apoptosis induction by TNF-family death receptors. Oncogene. 2003;22(53):8628–33.

    Article  CAS  PubMed  Google Scholar 

  25. Rowinsky EK. Targeted induction of apoptosis in cancer management: the emerging role of tumor necrosis factor-related apoptosis-inducing ligand receptor activating agents. J Clin Oncol: official journal of the American Society of Clinical Oncology. 2005;23(36):9394–407.

    Article  CAS  Google Scholar 

  26. Piechocki MP, Wu GS, Jones RF, Jacob JB, Gibson H, Ethier SP, et al. Induction of proapoptotic antibodies to triple-negative breast cancer by vaccination with TRAIL death receptor DR5 DNA. Int J Cancer. 2012;131(11):2562–72.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Takeda K, Yamaguchi N, Akiba H, Kojima Y, Hayakawa Y, Tanner JE, et al. Induction of tumor-specific T cell immunity by anti-DR5 antibody therapy. J Exp Med. 2004;199(4):437–48.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Chattergoon MA, Muthumani K, Tamura Y, Ramanathan M, Shames JP, Saulino V, et al. DR5 activation of caspase-8 induces DC maturation and immune enhancement in vivo. Mol Ther. 2008;16(2):419–26.

    Article  CAS  PubMed  Google Scholar 

  29. Wilson NS, Yang B, Yang A, Loeser S, Marsters S, Lawrence D, et al. An Fcgamma receptor-dependent mechanism drives antibody-mediated target-receptor signaling in cancer cells. Cancer Cell. 2011;19(1):101–13.

    Article  CAS  PubMed  Google Scholar 

  30. Lee BS, Kang SU, Hwang HS, Kim YS, Sung ES, Shin YS, et al. An agonistic antibody to human death receptor 4 induces apoptotic cell death in head and neck cancer cells through mitochondrial ROS generation. Cancer Lett. 2012;322(1):45–57.

    Article  CAS  PubMed  Google Scholar 

  31. Lee B, Cha H, Shin Y, Kim Y, Kim C. AY4, an agonistic anti-death receptor 4 MAB, induces apoptotic cell death in anaplastic thyroid cancer cells via downregulation of Bcl-xL with reactive oxygen species generation. Endocrine-related cancer. 2013;20(3).

  32. Greco FA, Bonomi P, Crawford J, Kelly K, Oh Y, Halpern W, et al. Phase 2 study of mapatumumab, a fully human agonistic monoclonal antibody which targets and activates the TRAIL receptor-1, in patients with advanced non-small cell lung cancer. Lung cancer (Amsterdam, Netherlands). 2008;61(1):82–90.

    Article  Google Scholar 

  33. Mom CH, Verweij J, Oldenhuis CNAM. Mapatumumab, a fully human agonistic monoclonal antibody that targets TRAIL-R1, in combination with gemcitabine and cisplatin: a phase I study. Clin Cancer Res. 2009;15(17):5584–90.

    Article  CAS  PubMed  Google Scholar 

  34. Rahman M, Davis SR, Pumphrey JG, Bao J, Nau MM, Meltzer PS, et al. TRAIL induces apoptosis in triple-negative breast cancer cells with a mesenchymal phenotype. Breast Cancer Res Treat. 2009;113(2):217–30.

    Article  PubMed  Google Scholar 

  35. Shi J, Zheng D, Liu Y, Sham MH, Tam P, Farzaneh F, et al. Overexpression of soluble TRAIL induces apoptosis in human lung adenocarcinoma and inhibits growth of tumor xenografts in nude mice. Cancer Res. 2005;65(5):1687–92.

    Article  CAS  PubMed  Google Scholar 

  36. Clancy L, Mruk K, Archer K, Woelfel M, Mongkolsapaya J, Screaton G, et al. Preligand assembly domain-mediated ligand-independent association between TRAIL receptor 4 (TR4) and TR2 regulates TRAIL-induced apoptosis. Proc Natl Acad Sci USA. 2005;102(50):18099–104.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Yada A, Yazawa M, Ishida S, Yoshida H, Ichikawa K, Kurakata S, et al. A novel humanized anti-human death receptor 5 antibody CS-1008 induces apoptosis in tumor cells without toxicity in hepatocytes. Ann Oncol. 2008;19(6):1060–7.

    Article  CAS  PubMed  Google Scholar 

  38. Ichikawa K, Liu W, Zhao L, Wang Z, Liu D, Ohtsuka T, et al. Tumoricidal activity of a novel anti-human DR5 monoclonal antibody without hepatocyte cytotoxicity. Nat Med. 2001;7(8):954–60.

    Article  CAS  PubMed  Google Scholar 

  39. Buchsbaum DJ, Zhou T, Grizzle WE, Oliver PG, Hammond CJ, Zhang S, et al. Antitumor efficacy of TRA-8 anti-DR5 monoclonal antibody alone or in combination with chemotherapy and/or radiation therapy in a human breast cancer model. Clin Cancer Res. 2003;9(10 Pt 1):3731–41.

    CAS  PubMed  Google Scholar 

  40. Oliver PG, LoBuglio AF, Zhou T, Forero A, Kim H, Zinn KR, et al. Effect of anti-DR5 and chemotherapy on basal-like breast cancer. Breast Cancer Res Treat. 2012;133(2):417–26.

    Article  CAS  PubMed  Google Scholar 

  41. Londono-Joshi AI, Oliver PG, Li Y, Lee CH, Forero-Torres A, LoBuglio AF, et al. Basal-like breast cancer stem cells are sensitive to anti-DR5 mediated cytotoxicity. Breast Cancer Res Treat. 2012;133(2):437–45.

    Article  CAS  PubMed  Google Scholar 

  42. Forero-Torres A, Varley KE, Abramson VG, Li Y, Vaklavas C, Lin NU, et al. TBCRC 019: a phase II trial of nanoparticle albumin-bound paclitaxel with or without the anti-death receptor 5 monoclonal antibody tigatuzumab in patients with triple-negative breast cancer. Clin Cancer Res. 2015;21(12):2722–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Lu M, Marsters S, Ye X, Luis E, Gonzalez L, Ashkenazi A. E-cadherin couples death receptors to the cytoskeleton to regulate apoptosis. Molecular cell. 2014;54(6).

  44. Allen JE, Kline CLB, Prabhu VV, Wagner J, Ishizawa J, Madhukar N, et al. Discovery and clinical introduction of first-in-class imipridone ONC201. Oncotarget. 2016;7(45):74380–92.

    Article  PubMed  PubMed Central  Google Scholar 

  45. Allen J, Krigsfeld G, Mayes P, Patel L, Dicker D, Patel A, et al. Dual inactivation of Akt and ERK by TIC10 Signals Foxo3a nuclear translocation, TRAIL gene induction, and potent antitumor effects. Sci Transl Med. 2013;5(171):171ra17.

    Article  PubMed  PubMed Central  Google Scholar 

  46. •• Ishizawa J, Zarabi S, Davis R, Halgas O, Nii T, Jitkova Y, et al. Mitochondrial ClpP-mediated proteolysis induces selective cancer cell lethality. Cancer cell. 2019;35(5). (This study found a direct mechanism of action of one of the most promising extrinsic apoptosis inducing agent ONC201, potentially opening a new avenue of apoptosis-targeted cancer therapeutics.)

  47. Ishizawa J, Kojima K, Chachad D, Ruvolo P, Ruvolo V, Jacamo RO, et al. ATF4 induction through an atypical integrated stress response to ONC201 triggers p53-independent apoptosis in hematological malignancies. Sci Signal. 2016;9(415):ra17.

    Article  PubMed  PubMed Central  Google Scholar 

  48. Wagner J, Kline CL, Zhou L, Campbell KS, MacFarlane AW, Olszanski AJ, et al. Dose intensification of TRAIL-inducing ONC201 inhibits metastasis and promotes intratumoral NK cell recruitment. J Clin Invest. 2018;128(6):2325–38.

    Article  PubMed  PubMed Central  Google Scholar 

  49. Cheng E, Wei M, Weiler S, Flavell R, Mak T, Lindsten T, et al. BCL-2, BCL-X(L) sequester BH3 domain-only molecules preventing BAX- and. Mol Cell. 2001;8(3):705–11.

    Article  CAS  PubMed  Google Scholar 

  50. Green DR. Cancer and apoptosis: Who Is Built to Last? Cancer Cell. 2017;31(1):2–4.

    Article  CAS  PubMed  Google Scholar 

  51. LaCasse E, Baird S, Korneluk R, MacKenzie A. The inhibitors of apoptosis (IAPs) and their emerging role in cancer. Oncogene. 1999;17(25).

  52. Arnt CR, Chiorean MV, Heldebrant MP, Gores GJ, Kaufmann SH. Synthetic Smac/DIABLO peptides enhance the effects of chemotherapeutic agents by binding XIAP and cIAP1 in situ. J Biol Chem. 2002;277(46):44236–43.

    Article  CAS  PubMed  Google Scholar 

  53. Zarnegar BJ, Wang Y, Mahoney DJ, Dempsey PW, Cheung HH, He J, et al. Noncanonical NF-kappaB activation requires coordinated assembly of a regulatory complex of the adaptors cIAP1, cIAP2, TRAF2 and TRAF3 and the kinase NIK. Nat Immunol. 2008;9(12):1371–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Cerna D, Lim B, Adelabu Y, Yoo S, Carter D, Fahim A, et al. SMAC mimetic/IAP inhibitor birinapant enhances radiosensitivity of glioblastoma multiforme. Radiat Res. 2021;195(6):549–60.

    Article  CAS  PubMed  Google Scholar 

  55. Vucic D, Dixit VM, Wertz IE. Ubiquitylation in apoptosis: a post-translational modification at the edge of life and death. Nat Rev Mol Cell Biol. 2011;12(7):439–52.

    Article  CAS  PubMed  Google Scholar 

  56. Sun C, Cai M, Gunasekera AH, Meadows RP, Wang H, Chen J, et al. NMR structure and mutagenesis of the inhibitor-of-apoptosis protein XIAP. Nature. 1999;401(6755):818–22.

    Article  CAS  PubMed  Google Scholar 

  57. Pemmaraju N, Carter B, Kantarjian H, Cortes J, Kadia T, Garcia-Manero GD, CD, et al. Results for phase II clinical trial of LCL161, a SMAC mimetic, in patients with primary myelofibrosis (PMF), post-polycythemia vera myelofibrosis (post-PV MF) or post-essential thrombocytosis myelofibrosis (post-ET MF). ASH 58th Annual Meeting & Exposition Proceedings. 2016;Blood 2016 128:3105.

  58. Infante J, Dees E, Olszanski A, Dhuria S, Sen S, Cameron S, et al. Phase I dose-escalation study of LCL161, an oral inhibitor of apoptosis proteins inhibitor, in patients with advanced solid tumors. J Clin Oncol: official journal of the American Society of Clinical Oncology. 2014.

  59. Gerges S, Rohde K, Fulda S. Cotreatment with Smac mimetics and demethylating agents induces both apoptotic and necroptotic cell death pathways in acute lymphoblastic leukemia cells. Cancer Lett. 2016;375(1):127–32.

    Article  CAS  PubMed  Google Scholar 

  60. L Vidal R, Dees E, Chia S. A phase Ib study of LCL161, an oral inhibitor of apoptosis (IAP) antagonist, in combination with weekly paclitaxel in patients with advanced solid tumors. Cancer Research. 2012;72(24, Suppl 3).

  61. Pemmaraju N, Carter BZ, Kantarjian HM, Cortes JE, Bose P, Kadia TM, et al. Final results of phase 2 clinical trial of LCL161, a novel oral SMAC mimetic/IAP antagonist, for patients with intermediate to high risk myelofibrosis. Blood. 2019;134(Supplement_1):555.

    Article  Google Scholar 

  62. Qin Q, Zuo Y, Yang X, Lu J, Zhan L, L X, et al. Smac mimetic compound LCL161 sensitizes esophageal carcinoma cells to radiotherapy by inhibiting the expression of inhibitor of apoptosis protein. Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine. 2014;35(3).

  63. Yang L, Kumar B, Shen C, Zhao S, Blakaj D, Li T, et al. LCL161, a SMAC-mimetic, preferentially radiosensitizes human papillomavirus-negative head and neck squamous cell carcinoma. Molecular cancer therapeutics. 2019;18(6).

  64. Condon SM, Mitsuuchi Y, Deng Y, LaPorte MG, Rippin SR, Haimowitz T, et al. Birinapant, a smac-mimetic with improved tolerability for the treatment of solid tumors and hematological malignancies. J Med Chem. 2014;57(9):3666–77.

    Article  CAS  PubMed  Google Scholar 

  65. Benetatos CA, Mitsuuchi Y, Burns JM, Neiman EM, Condon SM, Yu G, et al. Birinapant (TL32711), a bivalent SMAC mimetic, targets TRAF2-associated cIAPs, abrogates TNF-induced NF-kappaB activation, and is active in patient-derived xenograft models. Mol Cancer Ther. 2014;13(4):867–79.

    Article  CAS  PubMed  Google Scholar 

  66. Carter BZ, Mak PY, Mak DH, Shi Y, Qiu Y, Bogenberger JM, et al. Synergistic targeting of AML stem/progenitor cells with IAP antagonist birinapant and demethylating agents. J Natl Cancer Inst. 2014;106(2):djt440.

    Article  PubMed  PubMed Central  Google Scholar 

  67. Min DJ, He S, Green JE. Birinapant (TL32711) Improves responses to GEM/AZD7762 combination therapy in triple-negative breast cancer cell lines. Anticancer Res. 2016;36(6):2649–57.

    CAS  PubMed  PubMed Central  Google Scholar 

  68. Amaravadi RK, Schilder RJ, Martin LP, Levin M, Graham MA, Weng DE, et al. A phase I study of the SMAC-mimetic birinapant in adults with refractory solid tumors or lymphoma. Mol Cancer Ther. 2015;14(11):2569–75.

    Article  CAS  PubMed  Google Scholar 

  69. Amaravadi RK, Senzer NN, Martin LP, Schilder RJ, LoRusso P, Papadopoulos KP, et al. A phase I study of birinapant (TL32711) combined with multiple chemotherapies evaluating tolerability and clinical activity for solid tumor patients. J Clin Oncol. 2013;31(15_suppl):2504.

    Article  Google Scholar 

  70. Ward GA, Lewis EJ, Ahn JS, Johnson CN, Lyons JF, Martins V, et al. ASTX660, a novel non-peptidomimetic antagonist of cIAP1/2 and XIAP, potently induces TNFalpha-dependent apoptosis in cancer cell lines and inhibits tumor growth. Mol Cancer Ther. 2018;17(7):1381–91.

    Article  CAS  PubMed  Google Scholar 

  71. Wiechno P, Somer BG, Mellado B, Chlosta PL, Cervera Grau JM, Castellano D, et al. A randomised phase 2 study combining LY2181308 sodium (survivin antisense oligonucleotide) with first-line docetaxel/prednisone in patients with castration-resistant prostate cancer. Eur Urol. 2014;65(3):516–20.

    Article  CAS  PubMed  Google Scholar 

  72. Natale R, Blackhall F, Kowalski D, Ramlau R, Bepler G, Grossi F, et al. Evaluation of antitumor activity using change in tumor size of the survivin antisense oligonucleotide LY2181308 in combination with docetaxel for second-line treatment of patients with non-small-cell lung cancer: a randomized open-label phase II study. J Thorac Oncol: official publication of the International Association for the study of lung cancer. 2014;9(11):1704–8.

    Article  CAS  Google Scholar 

  73. Yu Y, Zhao X, Zhang Y, Kang Y, Wang J, Liu Y. Antitumor activity of YM155, a selective survivin suppressant, in combination with cisplatin in hepatoblastoma. Oncol Rep. 2015;34(1):407–14.

    Article  CAS  PubMed  Google Scholar 

  74. Fenstermaker RA, Ciesielski MJ, Qiu J, Yang N, Frank CL, Lee KP, et al. Clinical study of a survivin long peptide vaccine (SurVaxM) in patients with recurrent malignant glioma. Cancer Immunol Immunother CII. 2016;65(11):1339–52.

    Article  CAS  PubMed  Google Scholar 

  75. Dorigo O, Fiset S, MacDonald L, Bramhecha Y, Hrytsenko O, Dirk B, et al. DPX-Survivac, a novel T-cell immunotherapy, to induce robust T-cell responses in advanced ovarian cancer. https://doi.org/10.1200/JCO.2020.38.5_suppl.6

  76. Goodwin CM, Rossanese OW, Olejniczak ET, Fesik SW. Myeloid cell leukemia-1 is an important apoptotic survival factor in triple-negative breast cancer. Cell Death Differ. 2015.

  77. Yang L, Perez AA, Fujie S, Warden C, Li J, Wang Y, et al. Wnt modulates MCL1 to control cell survival in triple negative breast cancer. BMC Cancer. 2014;14:124.

    Article  PubMed  PubMed Central  Google Scholar 

  78. Petrocca F, Altschuler G, Tan SM, Mendillo ML, Yan H, Jerry DJ, et al. A genome-wide siRNA screen identifies proteasome addiction as a vulnerability of basal-like triple-negative breast cancer cells. Cancer Cell. 2013;24(2):182–96.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Wei G, Margolin AA, Haery L, Brown E, Cucolo L, Julian B, et al. Chemical genomics identifies small-molecule MCL1 repressors and BCL-xL as a predictor of MCL1 dependency. Cancer Cell. 2012;21(4):547–62.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Liu X, Tang H, Chen J, Song C, Yang L, Liu P, et al. MicroRNA-101 inhibits cell progression and increases paclitaxel sensitivity by suppressing MCL-1 expression in human triple-negative breast cancer. Oncotarget. 2015;6(24):20070–83.

    Article  PubMed  PubMed Central  Google Scholar 

  81. Balko JM, Giltnane JM, Wang K, Schwarz LJ, Young CD, Cook RS, et al. Molecular profiling of the residual disease of triple-negative breast cancers after neoadjuvant chemotherapy identifies actionable therapeutic targets. Cancer Discov. 2014;4(2):232–45.

    Article  CAS  PubMed  Google Scholar 

  82. Ding Q, He X, Xia W, Hsu JM, Chen CT, Li LY, et al. Myeloid cell leukemia-1 inversely correlates with glycogen synthase kinase-3beta activity and associates with poor prognosis in human breast cancer. Cancer Res. 2007;67(10):4564–71.

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

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

    Article  PubMed  PubMed Central  Google Scholar 

  85. Boiani M, Daniel C, Liu X, Hogarty MD, Marnett LJ. The stress protein BAG3 stabilizes Mcl-1 protein and promotes survival of cancer cells and resistance to antagonist ABT-737. J Biol Chem. 2013;288(10):6980–90.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Abulwerdi F, Liao C, Liu M, Azmi AS, Aboukameel A, Mady AS, et al. A novel small-molecule inhibitor of mcl-1 blocks pancreatic cancer growth in vitro and in vivo. Mol Cancer Ther. 2014;13(3):565–75.

    Article  CAS  PubMed  Google Scholar 

  87. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Mitchell C, Yacoub A, Hossein H, Martin AP, Bareford MD, Eulitt P, et al. Inhibition of MCL-1 in breast cancer cells promotes cell death in vitro and in vivo. Cancer Biol Ther. 2010;10(9):903–17.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Torres-Adorno AM, Lee J, Kogawa T, Ordentlich P, Tripathy D, Lim B, et al. Histone deacetylase inhibitor enhances the efficacy of MEK inhibitor through NOXA-mediated MCL1 degradation in triple-negative and inflammatory breast cancer. Clin Cancer Res. 2017;23(16):4780–92.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Ploner C, Kofler R, Villunger A. Noxa: at the tip of the balance between life and death. Oncogene. 2008;27(Suppl 1):S84-92.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  92. Dettman EW, SL; Doykan, C; Arn, M; Blake, N; Bearss, DJ; Cardone, M; Smith, BD editor mitochondrial profiling in AML patients treated with an alvocidib containing regimen reveals MCL1 dependency in responder bone marrow. Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 2015 Apr 18–22; Philadelphia, PA: AACR.

  93. Whatcott C, editor The MCL-1 targeting effect of alvocidib potentiates the activity of cytarabine and mitoxantrone in a time-sequential regimen in AML. SOHO 2015 Annual Meeting; 2015 2015, Sept-16; Houston, TX.

  94. Pecot J, Maillet L, Le Pen J, Vuillier C, Trecesson SC, Fetiveau A, et al. Tight sequestration of BH3 proteins by BCL-xL at subcellular membranes contributes to apoptotic resistance. Cell Rep. 2016;17(12):3347–58.

    Article  CAS  PubMed  Google Scholar 

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

    Article  PubMed  Google Scholar 

  96. 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(4):311–22.

    Article  CAS  PubMed  Google Scholar 

  97. Seymour JF, Ma S, Brander DM, Choi MY, Barrientos J, Davids MS, et al. Venetoclax plus rituximab in relapsed or refractory chronic lymphocytic leukaemia: a phase 1b study. Lancet Oncol. 2017;18(2):230–40.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Elledge RM, Green S, Howes L, Clark GM, Berardo M, Allred DC, et al. bcl-2, p53, and response to tamoxifen in estrogen receptor-positive metastatic breast cancer: a Southwest Oncology Group study. J Clin Oncol: official journal of the American Society of Clinical Oncology. 1997;15(5):1916–22.

    Article  CAS  Google Scholar 

  99. • Lindeman G, Hamilton E, Krop I, Lim B, Modi S, Saura C, et al. Abstract OT-28–03: VICKI: a phase Ib/II, randomized, placebo-controlled, study of venetoclax plus ado-trastuzumab emtansine (T-DM1) in patients (pts) with previously treated HER2-positive locally advanced (LA) or metastatic breast cancer (MBC). 2021;81(4_suppl). (One of the first studies in solid tumor showing the potential synergy of Bcl-2 inhibitor and standard anti-Her2 therapy. This study provided excitement and rationale to investigate Bcl-2 inhibitors in solid tumors.)

  100. Lindeman GJ, Bowen R, Jerzak KJ, Song X, Decker T, Boyle FM, et al. Results from VERONICA: a randomized, phase II study of second-/third-line venetoclax (VEN) + fulvestrant (F) versus F alone in estrogen receptor (ER)-positive, HER2-negative, locally advanced, or metastatic breast cancer (LA/MBC). https://doi.org/10.1200/JCO.2021.39.15_suppl.1004. 2021;39(15_suppl.).

  101. Goy A, Hernandez-Ilzaliturri FJ, Kahl B, Ford P, Protomastro E, Berger M. A phase I/II study of the pan Bcl-2 inhibitor obatoclax mesylate plus bortezomib for relapsed or refractory mantle cell lymphoma. Leuk Lymphoma. 2014;55(12):2761–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Lagares D, Santos A, Grasberger PE, Liu F, Probst CK, Rahimi RA, et al. Targeted apoptosis of myofibroblasts with the BH3 mimetic ABT-263 reverses established fibrosis. Sci Transl Med. 2017;9(420).

  103. 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(26):7145–54.

    Article  CAS  PubMed  Google Scholar 

  104. • Pullarkat V, Lacayo N, Jabbour E, Rubnitz J, Bajel A, Laetsch T, et al. Venetoclax and navitoclax in combination with chemotherapy in patients with relapsed or refractory acute lymphoblastic leukemia and lymphoblastic lymphoma. Cancer discovery. 2021;11(6). (A study showing the clinical efficacy of combined Bcl-2 inhibitor and Bcl-xL inhibitor in hematological malignancy opened a case for potential synergy by combining inhibitors of the same BH3 domain sharing Bcl-2 family proteins.)

  105. Gong J, Costanzo A, Yang H-Q, Melino G, Kaelin WG, Levrero M, et al. The tyrosine kinase c-Abl regulates p73 in apoptotic response to cisplatin-induced DNA damage. Nature. 1999;399(6738):806–9.

    Article  CAS  PubMed  Google Scholar 

  106. Zhang X, Tang N, Hadden TJ, Rishi AK. Akt, FoxO and regulation of apoptosis. Biochem Biophys Acta. 2011;1813(11):1978–86.

    Article  CAS  PubMed  Google Scholar 

  107. Lane DP. Cancer. p53, guardian of the genome. Nature. 1992;358(6381):15–6.

  108. Oliner JD, Saiki AY, Caenepeel S. The role of MDM2 amplification and overexpression in tumorigenesis. Cold Spring Harb Perspect Med. 2016;6(6):a026336.

    Article  PubMed  PubMed Central  Google Scholar 

  109. Trino S, De Luca L, Laurenzana I, Caivano A, Del Vecchio L, Martinelli G, et al. P53-MDM2 pathway: evidences for a new targeted therapeutic approach in B-acute lymphoblastic leukemia. Front Pharmacol. 2016;7:491.

    Article  PubMed  PubMed Central  Google Scholar 

  110. Joshi K, Banasavadi-Siddegowda Y, Mo X, Kim SH, Mao P, Kig C, et al. MELK-dependent FOXM1 phosphorylation is essential for proliferation of glioma stem cells. Stem Cells. 2013;31(6):1051–63.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Li S, Li Z, Guo T, Xing XF, Cheng X, Du H, et al. Maternal embryonic leucine zipper kinase serves as a poor prognosis marker and therapeutic target in gastric cancer. Oncotarget. 2016;7(5):6266–80.

    Article  PubMed  Google Scholar 

  112. Wang Y, Lee YM, Baitsch L, Huang A, Xiang Y, Tong H, et al. MELK is an oncogenic kinase essential for mitotic progression in basal-like breast cancer cells. Elife. 2014;3:e01763.

    Article  PubMed  PubMed Central  Google Scholar 

  113. Lizcano JM, Goransson O, Toth R, Deak M, Morrice NA, Boudeau J, et al. LKB1 is a master kinase that activates 13 kinases of the AMPK subfamily, including MARK/PAR-1. EMBO J. 2004;23(4):833–43.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Sun X, Gao L, Chien HY, Li WC, Zhao J. The regulation and function of the NUAK family. J Mol Endocrinol. 2013;51(2):R15-22.

    Article  CAS  PubMed  Google Scholar 

  115. Heyer BS, Warsowe J, Solter D, Knowles BB, Ackerman SL. New member of the Snf1/AMPK kinase family, Melk, is expressed in the mouse egg and preimplantation embryo. Mol Reprod Dev. 1997;47(2):148–56.

    Article  CAS  PubMed  Google Scholar 

  116. Speers C, Zhao SG, Kothari V, Santola A, Liu M, Wilder-Romans K, et al. Maternal embryonic leucine zipper kinase (MELK) as a novel mediator and biomarker of radioresistance in human breast cancer. Clin Cancer Res. 2016;22(23):5864–75.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Du T, Qu Y, Li J, Li H, Su L, Zhou Q, et al. Maternal embryonic leucine zipper kinase enhances gastric cancer progression via the FAK/Paxillin pathway. Mol Cancer. 2014;13:100.

    Article  PubMed  PubMed Central  Google Scholar 

  118. Ganguly R, Mohyeldin A, Thiel J, Kornblum HI, Beullens M, Nakano I. MELK-a conserved kinase: functions, signaling, cancer, and controversy. Clin Transl Med. 2015;4:11.

    Article  PubMed  PubMed Central  Google Scholar 

  119. Inoue H, Kato T, Olugbile S, Tamura K, Chung S, Miyamoto T, et al. Effective growth-suppressive activity of maternal embryonic leucine-zipper kinase (MELK) inhibitor against small cell lung cancer. Oncotarget. 2016;7(12):13621–33.

    Article  PubMed  PubMed Central  Google Scholar 

  120. Kato T, Inoue H, Imoto S, Tamada Y, Miyamoto T, Matsuo Y, et al. Oncogenic roles of TOPK and MELK, and effective growth suppression by small molecular inhibitors in kidney cancer cells. Oncotarget. 2016;7(14):17652–64.

    Article  PubMed  PubMed Central  Google Scholar 

  121. Pickard MR, Green AR, Ellis IO, Caldas C, Hedge VL, Mourtada-Maarabouni M, et al. Dysregulated expression of Fau and MELK is associated with poor prognosis in breast cancer. Breast Cancer Res: BCR. 2009;11(4):R60.

    Article  PubMed  PubMed Central  Google Scholar 

  122. Tian S, Roepman P, Van’t Veer LJ, Bernards R, de Snoo F, Glas AM. Biological functions of the genes in the mammaprint breast cancer profile reflect the hallmarks of cancer. Biomark Insights. 2010;5:129–38.

    Article  PubMed  PubMed Central  Google Scholar 

  123. Parker JS, Mullins M, Cheang MC, Leung S, Voduc D, Vickery T, et al. Supervised risk predictor of breast cancer based on intrinsic subtypes. J Clin Oncol: official journal of the American Society of Clinical Oncology. 2009;27(8):1160–7.

    Article  Google Scholar 

  124. Hebbard LW, Maurer J, Miller A, Lesperance J, Hassell J, Oshima RG, et al. Maternal embryonic leucine zipper kinase is upregulated and required in mammary tumor-initiating cells in vivo. Cancer Res. 2010;70(21):8863–73.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  125. Kim SH, Joshi K, Ezhilarasan R, Myers TR, Siu J, Gu C, et al. EZH2 protects glioma stem cells from radiation-induced cell death in a MELK/FOXM1-dependent manner. Stem Cell Rep. 2015;4(2):226–38.

    Article  CAS  Google Scholar 

  126. Chen D, Zhou X, Lee T. Death-associated protein kinase 1 as a promising drug target in cancer and Alzheimer’s disease. Recent Pat Anti-Cancer Drug Discovery. 2019;14(2):144–57.

    Article  CAS  PubMed  Google Scholar 

  127. Wu YM, Chen ZJ, Jiang GM, Zhang KS, Liu Q, Liang SW, et al. Inverse agonist of estrogen-related receptor alpha suppresses the growth of triple negative breast cancer cells through ROS generation and interaction with multiple cell signaling pathways. Oncotarget. 2016;7(11):12568–81.

    Article  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

The manuscript was edited by Sarah Bronson, ELS, of the Research Medical Library at The University of Texas MD Anderson Cancer Center.

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Puneet Singh declares that she has no conflict of interest. Bora Lim has received research funding from Puma Biotechnology, Novartis, Genentech, Merck, and Takeda Oncology. There are no directly relevant financial activities related to the drugs included in this article.

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Singh, P., Lim, B. Targeting Apoptosis in Cancer. Curr Oncol Rep 24, 273–284 (2022). https://doi.org/10.1007/s11912-022-01199-y

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