Exploiting the pro-apoptotic function of NOXA as a therapeutic modality in cancer

References

• Boatright KM, Salvesen GS. Mechanisms of caspase activation. Curr Opin Cell Biol. 2003;15(6):725–731.
   PubMed Web of Science ®Google Scholar
• Strasser A, Cory S, Adams JM. Deciphering the rules of programmed cell death to improve therapy of cancer and other diseases. Embo J. 2011;30(18):3667–3683.
   PubMed Web of Science ®Google Scholar
• Gross A, Katz SG. Non-apoptotic functions of BCL-2 family proteins. Cell Death Differ. 2017.
   PubMed Web of Science ®Google Scholar
• Otsu K, Murakawa T, Yamaguchi O. BCL2L13 is a mammalian homolog of the yeast mitophagy receptor Atg32. Autophagy. 2015;11(10):1932–1933.
   PubMed Web of Science ®Google Scholar
• Schweers RL, Zhang J, Randall MS, et al. NIX is required for programmed mitochondrial clearance during reticulocyte maturation. Proc Natl Acad Sci U S A. 2007;104(49):19500–19505.
   PubMed Web of Science ®Google Scholar
• Li P, Nijhawan D, Budihardjo I, et al. Cytochrome c and dATP-dependent formation of Apaf-1/caspase-9 complex initiates an apoptotic protease cascade. Cell. 1997;91(4):479–489.
   PubMed Web of Science ®Google Scholar
• Tait SW, Green DR. Mitochondria and cell death: outer membrane permeabilization and beyond. Nat Rev Mol Cell Biol. 2010;11(9):621–632.
   PubMed Web of Science ®Google Scholar
• Czabotar PE, Lessene G, Strasser A, et al. Control of apoptosis by the BCL-2 protein family: implications for physiology and therapy. Nat Rev Mol Cell Biol. 2014;15(1):49–63.
   PubMed Web of Science ®Google Scholar
• Rooswinkel RW, Van De Kooij B, De Vries E, et al. Antiapoptotic potency of Bcl-2 proteins primarily relies on their stability, not binding selectivity. Blood. 2014;123(18):2806–2815.
   PubMed Web of Science ®Google Scholar
• Campbell KJ, Bath ML, Turner ML, et al. Elevated Mcl-1 perturbs lymphopoiesis, promotes transformation of hematopoietic stem/progenitor cells, and enhances drug resistance. Blood. 2010;116(17):3197–3207.
   PubMed Web of Science ®Google Scholar
• Strasser A, Harris AW, Cory S. bcl-2 transgene inhibits T cell death and perturbs thymic self-censorship. Cell. 1991;67(5):889–899.
   PubMed Web of Science ®Google Scholar
• Chen L, Willis SN, Wei A, et al. Differential targeting of prosurvival Bcl-2 proteins by their BH3-only ligands allows complementary apoptotic function. Mol Cell. 2005;17(3):393–403.
   PubMed Web of Science ®Google Scholar
• Willis SN, Chen L, Dewson G, et al. Proapoptotic Bak is sequestered by Mcl-1 and Bcl-xL, but not Bcl-2, until displaced by BH3-only proteins. Genes Dev. 2005;19(11):1294–1305.
   PubMed Web of Science ®Google Scholar
• Villunger A, Labi V, Bouillet P, et al. Can the analysis of BH3-only protein knockout mice clarify the issue of ‘direct versus indirect’ activation of Bax and Bak? Cell Death Differ. 2011;18(10):1545–1546.
   PubMed Web of Science ®Google Scholar
• Cheng EH, Wei MC, Weiler S, et al. BCL-2, BCL-X(L) sequester BH3 domain-only molecules preventing BAX- and BAK-mediated mitochondrial apoptosis. Mol Cell. 2001;8(3):705–711.
   PubMed Web of Science ®Google Scholar
• Ren D, Tu HC, Kim H, et al. BID, BIM, and PUMA are essential for activation of the BAX- and BAK-dependent cell death program. Science. 2010;330(6009):1390–1393.
   PubMed Web of Science ®Google Scholar
• Willis SN, Fletcher JI, Kaufmann T, et al. Apoptosis initiated when BH3 ligands engage multiple Bcl-2 homologs, not Bax or Bak. Science. 2007;315(5813):856–859.
   PubMed Web of Science ®Google Scholar
• Doerflinger M, Glab JA, Puthalakath H. BH3-only proteins: a 20-year stock-take. Febs J. 2015;282(6):1006–1016.
   PubMed Web of Science ®Google Scholar
• Gallenne T, Gautier F, Oliver L, et al. Bax activation by the BH3-only protein Puma promotes cell dependence on antiapoptotic Bcl-2 family members. J Cell Biol. 2009;185(2):279–290.
   PubMed Web of Science ®Google Scholar
• Chen HC, Kanai M, Inoue-Yamauchi A, et al. An interconnected hierarchical model of cell death regulation by the BCL-2 family. Nat Cell Biol. 2015;17(10):1270–1281.
   PubMed Web of Science ®Google Scholar
• Du H, Wolf J, Schafer B, et al. BH3 domains other than Bim and Bid can directly activate Bax/Bak. J Biol Chem. 2011;286(1):491–501. .
   PubMed Web of Science ®Google Scholar
• Dai H, Smith A, Meng XW, et al. Transient binding of an activator BH3 domain to the Bak BH3-binding groove initiates Bak oligomerization. J Cell Biol. 2011;194(1):39–48.
   PubMed Web of Science ®Google Scholar
• Moldoveanu T, Grace CR, Llambi F, et al. BID-induced structural changes in BAK promote apoptosis. Nat Struct Mol Biol. 2013;20(5):589–597.
   PubMed Web of Science ®Google Scholar
• Vogler M. BCL2A1: the underdog in the BCL2 family. Cell Death Differ. 2012;19(1):67–74.
   PubMed Web of Science ®Google Scholar
• Huhn AJ, Guerra RM, Harvey EP, et al. Selective covalent targeting of anti-apoptotic BFL-1 by cysteine-reactive stapled peptide inhibitors. Cell Chem Biol. 2016;23(9):1123–1134.
   PubMed Web of Science ®Google Scholar
• Barile E, Marconi GD, De SK, et al. hBfl-1/hNOXA interaction studies provide new insights on the role of Bfl-1 in cancer cell resistance and for the design of novel anticancer agents. ACS Chem Biol. 2017;12(2):444–455.
   PubMed Web of Science ®Google Scholar
• Zhong Q, Gao W, Du F, et al. Mule/ARF-BP1, a BH3-only E3 ubiquitin ligase, catalyzes the polyubiquitination of mcl-1 and regulates apoptosis. Cell. 2005;121(7):1085–1095.
   PubMed Web of Science ®Google Scholar
• Ding Q, He X, Hsu JM, et al. Degradation of Mcl-1 by beta-TrCP mediates glycogen synthase kinase 3-induced tumor suppression and chemosensitization. Mol Cell Biol. 2007;27(11):4006–4017.
   PubMed Web of Science ®Google Scholar
• Inuzuka H, Fukushima H, Shaik S, et al. Mcl-1 ubiquitination and destruction. Oncotarget. 2011;2(3):239–244.
   PubMed Web of Science ®Google Scholar
• Magiera MM, Mora S, Mojsa B, et al. Trim17-mediated ubiquitination and degradation of Mcl-1 initiate apoptosis in neurons. Cell Death Differ. 2013;20(2):281–292.
   PubMed Web of Science ®Google Scholar
• Schwickart M, Huang X, Lill JR, et al. Deubiquitinase USP9X stabilizes MCL1 and promotes tumour cell survival. Nature. 2010;463(7277):103–107.
   PubMed Web of Science ®Google Scholar
• Warr MR, Shore GC. Unique biology of Mcl-1: therapeutic opportunities in cancer. Curr Mol Med. 2008;8(2):138–147.
   PubMed Web of Science ®Google Scholar
• Song T, Wang Z, Ji F, et al. Deactivation of Mcl-1 by dual-function small-molecule inhibitors targeting the Bcl-2 homology 3 domain and facilitating Mcl-1 ubiquitination. Angewandte Chemie (International Ed in English). 2016;55(46):14250–14256.
   PubMed Web of Science ®Google Scholar
• Gomez-Bougie P, Menoret E, Juin P, et al. Noxa controls Mule-dependent Mcl-1 ubiquitination through the regulation of the Mcl-1/USP9X interaction. Biochem Biophys Res Commun. 2011;413(3):460–464.
   PubMed Web of Science ®Google Scholar
• Stankiewicz AR, Livingstone AM, Mohseni N, et al. Regulation of heat-induced apoptosis by Mcl-1 degradation and its inhibition by Hsp70. Cell Death Differ. 2009;16(4):638–647.
   PubMed Web of Science ®Google Scholar
• Pal A, Young MA, Donato NJ. Emerging potential of therapeutic targeting of ubiquitin-specific proteases in the treatment of cancer. Cancer Res. 2014;74(18):4955–4966.
   PubMed Web of Science ®Google Scholar
• Craxton A, Butterworth M, Harper N, et al. NOXA, a sensor of proteasome integrity, is degraded by 26S proteasomes by an ubiquitin-independent pathway that is blocked by MCL-1. Cell Death Differ. 2012;19(9):1424–1434.
   PubMed Web of Science ®Google Scholar
• Baou M, Kohlhaas SL, Butterworth M, et al. Role of NOXA and its ubiquitination in proteasome inhibitor-induced apoptosis in chronic lymphocytic leukemia cells. Haematologica. 2010;95(9):1510–1518.
   PubMed Web of Science ®Google Scholar
• Brinkmann K, Zigrino P, Witt A, et al. Ubiquitin C-terminal hydrolase-L1 potentiates cancer chemosensitivity by stabilizing NOXA. Cell Rep. 2013;3(3):881–891.
   PubMed Web of Science ®Google Scholar
• Zhou W, Xu J, Li H, et al. Neddylation E2 UBE2F promotes the survival of lung cancer cells by activating CRL5 to degrade NOXA via the K11 Linkage. Clin Cancer Res. 2017;23(4):1104–1116.
   PubMed Web of Science ®Google Scholar
• Wei D, Li H, Yu J, et al. Radiosensitization of human pancreatic cancer cells by MLN4924, an investigational NEDD8-activating enzyme inhibitor. Cancer Res. 2012;72(1):282–293.
   PubMed Web of Science ®Google Scholar
• Wang Y, Luo Z, Pan Y, et al. Targeting protein neddylation with an NEDD8-activating enzyme inhibitor MLN4924 induced apoptosis or senescence in human lymphoma cells. Cancer Biol Ther. 2015;16(3):420–429.
   PubMed Web of Science ®Google Scholar
• Godbersen JC, Humphries LA, Danilova OV, et al. The Nedd8-activating enzyme inhibitor MLN4924 thwarts microenvironment-driven NF-kappaB activation and induces apoptosis in chronic lymphocytic leukemia B cells. Clin Cancer Res. 2014;20(6):1576–1589.
   PubMed Web of Science ®Google Scholar
• Hijikata M, Kato N, Sato T, et al. Molecular cloning and characterization of a cDNA for a novel phorbol-12-myristate-13-acetate-responsive gene that is highly expressed in an adult T-cell leukemia cell line. J Virol. 1990;64(10):4632–4639.
   PubMed Web of Science ®Google Scholar
• Wang Z, Sun Y. Identification and characterization of two splicing variants of human Noxa. Anticancer Res. 2008;28(3a:1667–1674.
   Web of Science ®Google Scholar
• Ploner C, Kofler R, Noxa: VA. At the tip of the balance between life and death. Oncogene. 2008;27(Suppl 1):S84–S92.
   PubMed Web of Science ®Google Scholar
• Fei P, Bernhard EJ, El-Deiry WS. Tissue-specific induction of p53 targets in vivo. Cancer Res. 2002;62(24):7316–7327.
   PubMed Web of Science ®Google Scholar
• Oda E, Ohki R, Murasawa H, et al. Noxa, a BH3-only member of the Bcl-2 family and candidate mediator of p53-induced apoptosis. Science. 2000;288(5468):1053–1058.
   PubMed Web of Science ®Google Scholar
• Villunger A, Michalak EM, Coultas L, et al. p53- and drug-induced apoptotic responses mediated by BH3-only proteins puma and noxa. Science. 2003;302(5647):1036–1038.
   PubMed Web of Science ®Google Scholar
• Shibue T, Suzuki S, Okamoto H, et al. Differential contribution of Puma and Noxa in dual regulation of p53-mediated apoptotic pathways. Embo J. 2006;25(20):4952–4962.
   PubMed Web of Science ®Google Scholar
• Naik E, Michalak EM, Villunger A, et al. Ultraviolet radiation triggers apoptosis of fibroblasts and skin keratinocytes mainly via the BH3-only protein Noxa. J Cell Biol. 2007;176(4):415–424. .
   PubMed Web of Science ®Google Scholar
• Haschka MD, Soratroi C, Kirschnek S, et al. The NOXA-MCL1-BIM axis defines lifespan on extended mitotic arrest. Nat Commun. 2015;6:6891.
   PubMed Web of Science ®Google Scholar
• Diaz-Martinez LA, Karamysheva ZN, Warrington R, et al. Genome-wide siRNA screen reveals coupling between mitotic apoptosis and adaptation. Embo J. 2014;33(17):1960–1976.
   PubMed Web of Science ®Google Scholar
• Grande L, Bretones G, Rosa-Garrido M, et al. Transcription factors Sp1 and p73 control the expression of the proapoptotic protein NOXA in the response of testicular embryonal carcinoma cells to cisplatin. J Biol Chem. 2012;287(32):26495–26505.
   PubMed Web of Science ®Google Scholar
• Flinterman M, Guelen L, Ezzati-Nik S, et al. E1A activates transcription of p73 and Noxa to induce apoptosis. J Biol Chem. 2005;280(7):5945–5959.
   PubMed Web of Science ®Google Scholar
• Tonino SH, Van Laar J, van Oers MH, et al. ROS-mediated upregulation of Noxa overcomes chemoresistance in chronic lymphocytic leukemia. Oncogene. 2011;30(6):701–713.
   PubMed Web of Science ®Google Scholar
• Sheridan C, Brumatti G, Elgendy M, et al. An ERK-dependent pathway to Noxa expression regulates apoptosis by platinum-based chemotherapeutic drugs. Oncogene. 2010;29(49):6428–6441.
   PubMed Web of Science ®Google Scholar
• Yamashita M, Kuwahara M, Suzuki A, et al. Bmi1 regulates memory CD4 T cell survival via repression of the Noxa gene. J Exp Med. 2008;205(5):1109–1120.
   PubMed Web of Science ®Google Scholar
• Jones PA, Issa JP, Baylin S. Targeting the cancer epigenome for therapy. Nat Rev Genet. 2016;17(10):630–641.
   PubMed Web of Science ®Google Scholar
• Zhou L, Ruvolo VR, McQueen T, et al. HDAC inhibition by SNDX-275 (Entinostat) restores expression of silenced leukemia-associated transcription factors Nur77 and Nor1 and of key pro-apoptotic proteins in AML. Leukemia. 2013;27(6):1358–1368.
   PubMed Web of Science ®Google Scholar
• Perez-Perarnau A, Coll-Mulet L, Rubio-Patino C, et al. Analysis of apoptosis regulatory genes altered by histone deacetylase inhibitors in chronic lymphocytic leukemia cells. Epigenetics. 2011;6(10):1228–1235.
   PubMed Web of Science ®Google Scholar
• Carmeliet P, Dor Y, Herbert JM, et al. Role of HIF-1alpha in hypoxia-mediated apoptosis, cell proliferation and tumour angiogenesis. Nature. 1998;394(6692):485–490.
   PubMed Web of Science ®Google Scholar
• Kim JY, Ahn HJ, Ryu JH, et al. BH3-only protein Noxa is a mediator of hypoxic cell death induced by hypoxia-inducible factor 1alpha. J Exp Med. 2004;199(1):113–124.
   PubMed Web of Science ®Google Scholar
• Wouters BG, Koritzinsky M. Hypoxia signalling through mTOR and the unfolded protein response in cancer. Nat Rev Cancer. 2008;8(11):851–864.
   PubMed Web of Science ®Google Scholar
• Toth A, Nickson P, Mandl A, et al. Endoplasmic reticulum stress as a novel therapeutic target in heart diseases. Cardiovasc Hematol Disord Drug Targets. 2007;7(3):205–218.
   PubMedGoogle Scholar
• Puthalakath H, O’Reilly LA, Gunn P, et al. ER stress triggers apoptosis by activating BH3-only protein Bim. Cell. 2007;129(7):1337–1349.
   PubMed Web of Science ®Google Scholar
• Fribley AM, Evenchik B, Zeng Q, et al. Proteasome inhibitor PS-341 induces apoptosis in cisplatin-resistant squamous cell carcinoma cells by induction of Noxa. J Biol Chem. 2006;281(42):31440–31447.
   PubMed Web of Science ®Google Scholar
• Armstrong JL, Flockhart R, Veal GJ, et al. Regulation of endoplasmic reticulum stress-induced cell death by ATF4 in neuroectodermal tumor cells. J Biol Chem. 2010;285(9):6091–6100.
   PubMed Web of Science ®Google Scholar
• Albershardt TC, Salerni BL, Soderquist RS, et al. Multiple BH3 mimetics antagonize antiapoptotic MCL1 protein by inducing the endoplasmic reticulum stress response and up-regulating BH3-only protein NOXA. J Biol Chem. 2011;286(28):24882–24895.
   PubMed Web of Science ®Google Scholar
• Soderquist RS, Danilov AV, Eastman A. Gossypol increases expression of the pro-apoptotic BH3-only protein NOXA through a novel mechanism involving phospholipase A2, cytoplasmic calcium, and endoplasmic reticulum stress. J Biol Chem. 2014;289(23):16190–16199.
   PubMed Web of Science ®Google Scholar
• Kelly KR, Espitia CM, Mahalingam D, et al. Reovirus therapy stimulates endoplasmic reticular stress, NOXA induction, and augments bortezomib-mediated apoptosis in multiple myeloma. Oncogene. 2012;31(25):3023–3038.
   PubMed Web of Science ®Google Scholar
• Yan J, Zhong N, Liu G, et al. Usp9x- and Noxa-mediated Mcl-1 downregulation contributes to pemetrexed-induced apoptosis in human non-small-cell lung cancer cells. Cell Death Dis. 2014;5:e1316.
   PubMed Web of Science ®Google Scholar
• Davis AL, Qiao S, Lesson JL, et al. The quinone methide aurin is a heat shock response inducer that causes proteotoxic stress and Noxa-dependent apoptosis in malignant melanoma cells. J Biol Chem. 2015;290(3):1623–1638.
   PubMed Web of Science ®Google Scholar
• Soderquist RS, Eastman A. BCL2 inhibitors as anticancer drugs: a plethora of misleading BH3 mimetics. Mol Cancer Ther. 2016;15(9):2011–2017. .
   PubMed Web of Science ®Google Scholar
• Wang Q, Mora-Jensen H, Weniger MA, et al. ERAD inhibitors integrate ER stress with an epigenetic mechanism to activate BH3-only protein NOXA in cancer cells. Proc Natl Acad Sci U S A. 2009;106(7):2200–2205.
   PubMed Web of Science ®Google Scholar
• Obeng EA, Carlson LM, Gutman DM, et al. Proteasome inhibitors induce a terminal unfolded protein response in multiple myeloma cells. Blood. 2006;107(12):4907–4916. .
   PubMed Web of Science ®Google Scholar
• Gomez-Bougie P, Wuilleme-Toumi S, Menoret E, et al. Noxa up-regulation and Mcl-1 cleavage are associated to apoptosis induction by bortezomib in multiple myeloma. Cancer Res. 2007;67(11):5418–5424.
   PubMed Web of Science ®Google Scholar
• Qin JZ, Ziffra J, Stennett L, et al. Proteasome inhibitors trigger NOXA-mediated apoptosis in melanoma and myeloma cells. Cancer Res. 2005;65(14):6282–6293.
   PubMed Web of Science ®Google Scholar
• Perez-Galan P, Roue G, Villamor N, et al. The proteasome inhibitor bortezomib induces apoptosis in mantle-cell lymphoma through generation of ROS and Noxa activation independent of p53 status. Blood. 2006;107(1):257–264.
   PubMed Web of Science ®Google Scholar
• Narita T, Ri M, Masaki A, et al. Lower expression of activating transcription factors 3 and 4 correlates with shorter progression-free survival in multiple myeloma patients receiving bortezomib plus dexamethasone therapy. Blood Cancer J. 2015;5:e373.
   PubMed Web of Science ®Google Scholar
• Parlati F, Lee SJ, Aujay M, et al. Carfilzomib can induce tumor cell death through selective inhibition of the chymotrypsin-like activity of the proteasome. Blood. 2009;114(16):3439–3447.
   PubMed Web of Science ®Google Scholar
• Lamothe B, Wierda WG, Keating MJ, et al. Carfilzomib triggers cell death in chronic lymphocytic leukemia by inducing proapoptotic and endoplasmic reticulum stress responses. Clin Cancer Res. 2016;22(18):4712–4726.
   PubMed Web of Science ®Google Scholar
• Mannava S, Zhuang D, Nair JR, et al. KLF9 is a novel transcriptional regulator of bortezomib- and LBH589-induced apoptosis in multiple myeloma cells. Blood. 2012;119(6):1450–1458.
   PubMed Web of Science ®Google Scholar
• Desai S, Maurin M, Smith MA, et al. PRDM1 is required for mantle cell lymphoma response to bortezomib. Mol Cancer Res. 2010;8(6):907–918.
   PubMed Web of Science ®Google Scholar
• Maurer U, Charvet C, Wagman AS, et al. Glycogen synthase kinase-3 regulates mitochondrial outer membrane permeabilization and apoptosis by destabilization of MCL-1. Mol Cell. 2006;21(6):749–760.
   PubMed Web of Science ®Google Scholar
• Alves NL, Derks IA, Berk E, et al. The Noxa/Mcl-1 axis regulates susceptibility to apoptosis under glucose limitation in dividing T cells. Immunity. 2006;24(6):703–716.
   PubMed Web of Science ®Google Scholar
• Zhao Y, Altman BJ, Coloff JL, et al. Glycogen synthase kinase 3alpha and 3beta mediate a glucose-sensitive antiapoptotic signaling pathway to stabilize Mcl-1. Mol Cell Biol. 2007;27(12):4328–4339.
   PubMed Web of Science ®Google Scholar
• Wensveen FM, Alves NL, Derks IA, et al. Apoptosis induced by overall metabolic stress converges on the Bcl-2 family proteins Noxa and Mcl-1. Apoptosis. 2011;16(7):708–721.
   PubMed Web of Science ®Google Scholar
• Lowman XH, McDonnell MA, Kosloske A, et al. The proapoptotic function of Noxa in human leukemia cells is regulated by the kinase Cdk5 and by glucose. Mol Cell. 2010;40(5):823–833.
   PubMed Web of Science ®Google Scholar
• Gimenez-Cassina A, Danial NN. Noxa: a sweet twist to survival and more. Molecular Cell. 2010;40(5):687–688.
   PubMed Web of Science ®Google Scholar
• Santidrian AF, Gonzalez-Girones DM, Iglesias-Serret D, et al. AICAR induces apoptosis independently of AMPK and p53 through up-regulation of the BH3-only proteins BIM and NOXA in chronic lymphocytic leukemia cells. Blood. 2010;116(16):3023–3032.
   PubMed Web of Science ®Google Scholar
• Yang Z, Klionsky DJ. Eaten alive: a history of macroautophagy. Nat Cell Biol. 2010;12(9):814–822.
   PubMed Web of Science ®Google Scholar
• Galluzzi L, Pietrocola F, Bravo-San Pedro JM, et al. Autophagy in malignant transformation and cancer progression. Embo J. 2015;34(7):856–880.
   PubMed Web of Science ®Google Scholar
• Lindqvist LM, Simon AK, Baehrecke EH. Current questions and possible controversies in autophagy. Cell Death Disc. 2015;1:15036.
   PubMedGoogle Scholar
• Feng W, Huang S, Wu H, et al. Molecular basis of Bcl-xL’s target recognition versatility revealed by the structure of Bcl-xL in complex with the BH3 domain of Beclin-1. J Mol Biol. 2007;372(1):223–235.
   PubMed Web of Science ®Google Scholar
• Oberstein A, Jeffrey PD, Shi Y. Crystal structure of the Bcl-XL-Beclin 1 peptide complex: beclin 1 is a novel BH3-only protein. J Biol Chem. 2007;282(17):13123–13132.
   PubMed Web of Science ®Google Scholar
• Tormo D, Checinska A, Alonso-Curbelo D, et al. Targeted activation of innate immunity for therapeutic induction of autophagy and apoptosis in melanoma cells. Cancer Cell. 2009;16(2):103–114.
   PubMed Web of Science ®Google Scholar
• Elgendy M, Sheridan C, Brumatti G, et al. Oncogenic Ras-induced expression of Noxa and Beclin-1 promotes autophagic cell death and limits clonogenic survival. Molecular Cell. 2011;42(1):23–35.
   PubMed Web of Science ®Google Scholar
• Oltersdorf T, Elmore SW, Shoemaker AR, et al. An inhibitor of Bcl-2 family proteins induces regression of solid tumours. Nature. 2005;435(7042):677–681.
   PubMed Web of Science ®Google Scholar
• Delbridge AR, Grabow S, Strasser A, et al. Thirty years of BCL-2: translating cell death discoveries into novel cancer therapies. Nat Rev Cancer. 2016;16(2):99–109.
   PubMed Web of Science ®Google Scholar
• Mason KD, Carpinelli MR, Fletcher JI, et al. Programmed anuclear cell death delimits platelet life span. Cell. 2007;128(6):1173–1186.
   PubMed Web of Science ®Google Scholar
• Souers AJ, Leverson JD, Boghaert ER, et al. ABT-199, a potent and selective BCL-2 inhibitor, achieves antitumor activity while sparing platelets. Nat Med. 2013;19(2):202–208.
   PubMed Web of Science ®Google Scholar
• Roberts AW, Davids MS, Pagel JM, et al. Targeting BCL2 with venetoclax in relapsed chronic lymphocytic leukemia. N Engl J Med. 2016;374(4):311–322.
   PubMed Web of Science ®Google Scholar
• Lessene G, Czabotar PE, Sleebs BE, et al. Structure-guided design of a selective BCL-X(L) inhibitor. Nat Chem Biol. 2013;9(6):390–397.
   PubMed Web of Science ®Google Scholar
• Tao ZF, Hasvold L, Wang L, et al. Discovery of a potent and selective BCL-XL inhibitor with in vivo activity. ACS Med Chem Lett. 2014;5(10):1088–1093.
   PubMed Web of Science ®Google Scholar
• Bruncko M, Wang L, Sheppard GS, et al. Structure-guided design of a series of MCL-1 inhibitors with high affinity and selectivity. J Med Chem. 2015;58(5):2180–2194.
   PubMed Web of Science ®Google Scholar
• Leverson JD, Zhang H, Chen J, et al. Potent and selective small-molecule MCL-1 inhibitors demonstrate on-target cancer cell killing activity as single agents and in combination with ABT-263 (navitoclax). Cell Death Dis. 2015;6:e1590.
   PubMed Web of Science ®Google Scholar
• Kotschy A, Szlavik Z, Murray J, et al. The MCL1 inhibitor S63845 is tolerable and effective in diverse cancer models. Nature. 2016;538(7626):477–482.
   PubMed Web of Science ®Google Scholar
• Pierson W, Cauwe B, Policheni A, et al. Antiapoptotic Mcl-1 is critical for the survival and niche-filling capacity of Foxp3(+) regulatory T cells. Nat Immunol. 2013;14(9):959–965.
   PubMed Web of Science ®Google Scholar
• Fu NY, Rios AC, Pal B, et al. EGF-mediated induction of Mcl-1 at the switch to lactation is essential for alveolar cell survival. Nat Cell Biol. 2015;17(4):365–375.
   PubMed Web of Science ®Google Scholar
• Peperzak V, Vikstrom I, Walker J, et al. Mcl-1 is essential for the survival of plasma cells. Nat Immunol. 2013.
   PubMed Web of Science ®Google Scholar
• Vikstrom I, Carotta S, Luthje K, et al. Mcl-1 is essential for germinal center formation and B cell memory. Science. 2010;330(6007):1095–1099.
   PubMed Web of Science ®Google Scholar
• Akcay G, Belmonte MA, Aquila B, et al. Inhibition of Mcl-1 through covalent modification of a noncatalytic lysine side chain. Nat Chem Biol. 2016;12(11):931–936.
   PubMed Web of Science ®Google Scholar
• Lee S, Wales TE, Escudero S, et al. Allosteric inhibition of antiapoptotic MCL-1. Nat Struct Mol Biol. 2016;23(6):600–607.
   PubMed Web of Science ®Google Scholar
• Peperzak V, Slinger E, Ter Burg J, et al. Functional disparities among BCL-2 members in tonsillar and leukemic B-cell subsets assessed by BH3-mimetic profiling. Cell Death Differ. 2017;24(1):111–119.
   PubMed Web of Science ®Google Scholar
• Del Gaizo Moore V, Letai A. BH3 profiling–measuring integrated function of the mitochondrial apoptotic pathway to predict cell fate decisions. Cancer Lett. 2013;332(2):202–205.
   PubMed Web of Science ®Google Scholar
• Albert MC, Brinkmann K, Kashkar H. Noxa and cancer therapy: tuning up the mitochondrial death machinery in response to chemotherapy. Mol Cell Oncol. 2014;1(1):e29906.
   PubMedGoogle Scholar
• Bolomsky A, Schlangen K, Schreiner W, et al. Targeting of BMI-1 with PTC-209 shows potent anti-myeloma activity and impairs the tumour microenvironment. J Hematol Oncol. 2016;9:17.
   PubMed Web of Science ®Google Scholar
• Gomez-Bougie P, Amiot M. Apoptotic machinery diversity in multiple myeloma molecular subtypes. Front Immunol. 2013;4:467.
   PubMed Web of Science ®Google Scholar
• Bodet L, Menoret E, Descamps G, et al. BH3-only protein Bik is involved in both apoptosis induction and sensitivity to oxidative stress in multiple myeloma. Br J Cancer. 2010;103(12):1808–1814.
   PubMed Web of Science ®Google Scholar
• Derenne S, Monia B, Dean NM, et al. Antisense strategy shows that Mcl-1 rather than Bcl-2 or Bcl-x(L) is an essential survival protein of human myeloma cells. Blood. 2002;100(1):194–199.
   PubMed Web of Science ®Google Scholar
• Gong JN, Khong T, Segal D, et al. Hierarchy for targeting pro-survival BCL2 family proteins in multiple myeloma: pivotal role of MCL1. Blood. 2016.
   Web of Science ®Google Scholar
• Ponder KG, Matulis SM, Hitosugi S, et al. Dual inhibition of Mcl-1 by the combination of carfilzomib and TG02 in multiple myeloma. Cancer Biol Ther. 2016;17(7):769–777.
   PubMed Web of Science ®Google Scholar
• Kiziltepe T, Hideshima T, Catley L, et al. 5-Azacytidine, a DNA methyltransferase inhibitor, induces ATR-mediated DNA double-strand break responses, apoptosis, and synergistic cytotoxicity with doxorubicin and bortezomib against multiple myeloma cells. Mol Cancer Ther. 2007;6(6):1718–1727.
   PubMed Web of Science ®Google Scholar
• Tromp JM, Tonino SH, Elias JA, et al. Dichotomy in NF-kappaB signaling and chemoresistance in immunoglobulin variable heavy-chain-mutated versus unmutated CLL cells upon CD40/TLR9 triggering. Oncogene. 2010;29(36):5071–5082.
   PubMed Web of Science ®Google Scholar
• Herishanu Y, Perez-Galan P, Liu D, et al. The lymph node microenvironment promotes B-cell receptor signaling, NF-kappaB activation, and tumor proliferation in chronic lymphocytic leukemia. Blood. 2011;117(2):563–574.
   PubMed Web of Science ®Google Scholar
• Morales AA, Olsson A, Celsing F, et al. Expression and transcriptional regulation of functionally distinct Bmf isoforms in B-chronic lymphocytic leukemia cells. Leukemia. 2004;18(1):41–47.
   PubMed Web of Science ®Google Scholar
• Mackus WJ, Kater AP, Grummels A, et al. Chronic lymphocytic leukemia cells display p53-dependent drug-induced Puma upregulation. Leukemia. 2005;19(3):427–434.
   PubMed Web of Science ®Google Scholar
• Smit LA, Hallaert DY, Spijker R, et al. Differential Noxa/Mcl-1 balance in peripheral versus lymph node chronic lymphocitic leukemia cells correlates with survival capacity. Blood. 2007;109(4):1660–1668.
   PubMed Web of Science ®Google Scholar
• Byrd JC, Furman RR, Coutre SE, et al. Targeting BTK with ibrutinib in relapsed chronic lymphocytic leukemia. N Engl J Med. 2013;369(1):32–42.
   PubMed Web of Science ®Google Scholar
• E. ten Hacken, Burger JA. Molecular pathways: targeting the microenvironment in chronic lymphocytic leukemia–focus on the B-cell receptor. Clin Cancer Res. 2014;20(3):548–556.
   PubMed Web of Science ®Google Scholar
• Wensveen FM, Derks IA, Van Gisbergen KP, et al. BH3-only protein Noxa regulates apoptosis in activated B cells and controls high-affinity antibody formation. Blood. 2012;119(6):1440–1449.
   PubMed Web of Science ®Google Scholar
• Slinger E, Wensveen FM, Guikema JE, et al. Chronic lymphocytic leukemia development is accelerated in mice with deficiency of the pro-apoptotic regulator NOXA. Haematologica. 2016;101(9):e374–7.
   PubMed Web of Science ®Google Scholar
• Liu FT, Agrawal SG, Movasaghi Z, et al. Dietary flavonoids inhibit the anticancer effects of the proteasome inhibitor bortezomib. Blood. 2008;112(9):3835–3846.
   PubMed Web of Science ®Google Scholar
• Wickremasinghe RG. Why is CLL refractory to bortezomib? Blood. 2008;112(9):3540–3541.
   PubMed Web of Science ®Google Scholar
• Faderl S, Rai K, Gribben J, et al. Phase II study of single-agent bortezomib for the treatment of patients with fludarabine-refractory B-cell chronic lymphocytic leukemia. Cancer. 2006;107(5):916–924.
   PubMed Web of Science ®Google Scholar
• Tromp JM, Geest CR, Breij EC, et al. Tipping the Noxa/Mcl-1 balance overcomes ABT-737 resistance in chronic lymphocytic leukemia. Clin Cancer Res. 2012;18(2):487–498.
   PubMed Web of Science ®Google Scholar
• Thijssen R, Slinger E, Weller K, et al. Resistance to ABT-199 induced by microenvironmental signals in chronic lymphocytic leukemia can be counteracted by CD20 antibodies or kinase inhibitors. Haematologica. 2015.
   PubMed Web of Science ®Google Scholar
• Hallaert DY, Spijker R, Jak M, et al. Crosstalk among Bcl-2 family members in B-CLL: seliciclib acts via the Mcl-1/Noxa axis and gradual exhaustion of Bcl-2 protection. Cell Death Differ. 2007;14(11):1958–1967.
   PubMed Web of Science ®Google Scholar
• Wiernik PH. Alvocidib (flavopiridol) for the treatment of chronic lymphocytic leukemia. Expert Opin Investig Drugs. 2016;25(6):729–734.
   PubMed Web of Science ®Google Scholar
• De Rooij MF, Kuil A, Geest CR, et al. The clinically active BTK inhibitor PCI-32765 targets B-cell receptor- and chemokine-controlled adhesion and migration in chronic lymphocytic leukemia. Blood. 2012;119(11):2590–2594.
   PubMed Web of Science ®Google Scholar
• Spaargaren M, De Rooij MF, Kater AP, et al. BTK inhibitors in chronic lymphocytic leukemia: a glimpse to the future. Oncogene. 2015;34(19):2426–2436.
   PubMed Web of Science ®Google Scholar
• Eldering E, Peperzak V, ter Burg H, et al. Bcl-2 members as drug target and biomarkers for response to Ibrutinib and Venetoclax in CLL. Blood. 2016;128(22):2043.
   PubMed Web of Science ®Google Scholar
• Ohshima-Hosoyama S, Davare MA, Hosoyama T, et al. Bortezomib stabilizes NOXA and triggers ROS-associated apoptosis in medulloblastoma. J Neurooncol. 2011;105(3):475–483.
   PubMed Web of Science ®Google Scholar
• Tessoulin B, Descamps G, Moreau P, et al. PRIMA-1Met induces myeloma cell death independent of p53 by impairing the GSH/ROS balance. Blood. 2014;124(10):1626–1636.
   PubMed Web of Science ®Google Scholar