Overcoming drug resistance by targeting protein homeostasis in multiple myeloma

Abstract

Multiple myeloma (MM) is a plasma cell disorder typically characterized by abundant synthesis of clonal immunoglobulin or free light chains. Although incurable, a deeper understanding of MM pathobiology has fueled major therapeutical advances over the past two decades, significantly improving patient outcomes. Proteasome inhibitors, immunomodulatory drugs, and monoclonal antibodies are among the most effective anti-MM drugs, targeting not only the cancerous cells, but also the bone marrow microenvironment. However, de novo resistance has been reported, and acquired resistance is inevitable for most patients over time, leading to relapsed/refractory disease and poor outcomes. Sustained protein synthesis coupled with impaired/insufficient proteolytic mechanisms makes MM cells exquisitely sensitive to perturbations in protein homeostasis, offering us the opportunity to target this intrinsic vulnerability for therapeutic purposes. This review highlights the scientific rationale for the clinical use of FDA-approved and investigational agents targeting protein homeostasis in MM.

Keywords

Multiple myeloma / drug resistance / proteasome inhibitors / immunomodulatory drugs / proteostasis / endoplasmic reticulum stress / unfolded protein response

References

[1] Palumbo A.Multiple myeloma.N Engl J Med2011;364:1046-60

[2] Obeng EA,Gutman DM,Lee KP.Proteasome inhibitors induce a terminal unfolded protein response in multiple myeloma cells.Blood2006;107:4907-16 PMCID:PMC1895817

[3] Cenci S,Cascio P.Progressively impaired proteasomal capacity during terminal plasma cell differentiation.EMBO J2006;25:1104-13 PMCID:PMC1409720

[4] Sontag EM,Frydman J.Sorting out the trash: the spatial nature of eukaryotic protein quality control.Curr Opin Cell Biol2014;26:139-46 PMCID:PMC4204729

[5] Benbrook DM.Integration of autophagy, proteasomal degradation, unfolded protein response and apoptosis.Exp Oncol2012;34:286-97

[6] Verma R,Deshaies RJ.Harnessing the power of proteolysis for targeted protein inactivation.Mol Cell2020;77:446-60

[7] Richardson PG,Schuster MW.Assessment of Proteasome Inhibition for Extending Remissions (APEX) InvestigatorsBortezomib or high-dose dexamethasone for relapsed multiple myeloma.N Engl J Med2005;352:2487-98

[8] Hideshima T,Chauhan D.The proteasome inhibitor PS-341 inhibits growth, induces apoptosis, and overcomes drug resistance in human multiple myeloma cells.Cancer Res2001;61:3071-6

[9] San Miguel JF, Schlag R, Khuageva NK, et al; VISTA Trial Investigators. Bortezomib plus melphalan and prednisone for initial treatment of multiple myeloma.N Engl J Med2008;359:906-17

[10] Dobson CM.Principles of protein folding, misfolding and aggregation.Semin Cell Dev Biol2004;15:3-16

[11] Walter P.The unfolded protein response: from stress pathway to homeostatic regulation.Science2011;334:1081-6

[12] De Los Rios P, Ben-Zvi A, Slutsky O, Azem A, Goloubinoff P. Hsp70 chaperones accelerate protein translocation and the unfolding of stable protein aggregates by entropic pulling.Proc Natl Acad Sci U S A2006;103:6166-71 PMCID:PMC1458849

[13] Qian SB,Boellmann F,Patterson C.CHIP-mediated stress recovery by sequential ubiquitination of substrates and Hsp70.Nature2006;440:551-5 PMCID:PMC4112096

[14] Bianchi G,Cascio P.The proteasome load versus capacity balance determines apoptotic sensitivity of multiple myeloma cells to proteasome inhibition.Blood2009;113:3040-9

[15] Bianchi G,Anderson KC.Promising therapies in multiple myeloma.Blood2015;126:300-10 PMCID:PMC4560339

[16] Yewdell JW,Bennink JR.At the crossroads of cell biology and immunology: DRiPs and other sources of peptide ligands for MHC class I molecules.J Cell Sci2001;114:845-51

[17] Cenci S.Managing and exploiting stress in the antibody factory.FEBS Lett2007;581:3652-7

[18] Schubert U,Gibbs J,Yewdell JW.Rapid degradation of a large fraction of newly synthesized proteins by proteasomes.Nature2000;404:770-4

[19] Goldberg AL.Functions of the proteasome: the lysis at the end of the tunnel.Science1995;268:522-3

[20] Hershko A.The ubiquitin system.Annu Rev Biochem1998;67:425-79

[21] Orlowski RZ.Why proteasome inhibitors cannot ERADicate multiple myeloma.Cancer Cell2013;24:275-7 PMCID:PMC3863636

[22] Xu P,Seyfried NT.Quantitative proteomics reveals the function of unconventional ubiquitin chains in proteasomal degradation.Cell2009;137:133-45 PMCID:PMC2668214

[23] Weissman AM,Ciechanover A.The predator becomes the prey: regulating the ubiquitin system by ubiquitylation and degradation.Nat Rev Mol Cell Biol2011;12:605-20 PMCID:PMC3545438

[24] Coux O,Goldberg AL.Structure and functions of the 20S and 26S proteasomes.Annu Rev Biochem1996;65:801-47

[25] Bhattacharyya S,Mim C.Regulated protein turnover: snapshots of the proteasome in action.Nat Rev Mol Cell Biol2014;15:122-33 PMCID:PMC4384331

[26] Ferrington DA. Immunoproteasomes. The proteasomal system in aging and disease. Elsevier; 2012. p. 75-112.

[27] Kimura H,Takahashi M.New insights into the function of the immunoproteasome in immune and nonimmune cells.J Immunol Res2015;2015:541984 PMCID:PMC4617869

[28] Kuhn DJ,Bjorklund CC.Second generation proteasome inhibitors: carfilzomib and immunoproteasome-specific inhibitors (IPSIs).Curr Cancer Drug Targets2011;11:285-95

[29] Basler M,Bitzer A,Groettrup M.The immunoproteasome: a novel drug target for autoimmune diseases.Clin Exp Rheumatol2015;33:S74-9

[30] Kisselev AF.Proteasome inhibitors: from research tools to drug candidates.Chem Biol2001;8:739-58

[31] Adams J.The development of proteasome inhibitors as anticancer drugs.Cancer Cell2004;5:417-21

[32] Dimopoulos MA,Palumbo A.Carfilzomib and dexamethasone versus bortezomib and dexamethasone for patients with relapsed or refractory multiple myeloma (ENDEAVOR): a randomised, phase 3, open-label, multicentre study.Lancet Oncol2016;17:27-38

[33] Stewart AK,Dimopoulos MA.ASPIRE InvestigatorsCarfilzomib, lenalidomide, and dexamethasone for relapsed multiple myeloma.N Engl J Med2015;372:142-52

[34] Bianchi G.Molecular mechanisms of effectiveness of novel therapies in multiple myeloma.Leuk Lymphoma2013;54:229-41

[35] Hideshima T,Akiyama M.Molecular mechanisms mediating antimyeloma activity of proteasome inhibitor PS-341.Blood2003;101:1530-4

[36] Hideshima T,Chauhan D.Bortezomib induces canonical nuclear factor-kappaB activation in multiple myeloma cells.Blood2009;114:1046-52 PMCID:PMC2721785

[37] Mitsiades N,Richardson PG.The proteasome inhibitor PS-341 potentiates sensitivity of multiple myeloma cells to conventional chemotherapeutic agents: therapeutic applications.Blood2003;101:2377-80

[38] Fennell DA,Mutti L.BCL-2 family regulation by the 20S proteasome inhibitor bortezomib.Oncogene2008;27:1189-97

[39] Hideshima T,Chauhan D,Richardson P.Biologic sequelae of c-Jun NH(2)-terminal kinase (JNK) activation in multiple myeloma cell lines.Oncogene2003;22:8797-801

[40] Lee AH,Glimcher LH.XBP-1 regulates a subset of endoplasmic reticulum resident chaperone genes in the unfolded protein response.Mol Cell Biol2003;23:7448-59 PMCID:PMC207643

[41] Meister S,Neubert K.Extensive immunoglobulin production sensitizes myeloma cells for proteasome inhibition.Cancer Res2007;67:1783-92

[42] Sha Z.Proteasome-mediated processing of Nrf1 is essential for coordinate induction of all proteasome subunits and p97.Curr Biol2014;24:1573-83 PMCID:PMC4108618

[43] Vangala JR,Krüger E,Radhakrishnan SK.Nrf1 can be processed and activated in a proteasome-independent manner.Curr Biol2016;26:R834-5 PMCID:PMC6156719

[44] Radhakrishnan SK,Young P,Chan JY.Transcription factor Nrf1 mediates the proteasome recovery pathway after proteasome inhibition in mammalian cells.Mol Cell2010;38:17-28 PMCID:PMC2874685

[45] Radhakrishnan SK,Deshaies RJ.p97-dependent retrotranslocation and proteolytic processing govern formation of active Nrf1 upon proteasome inhibition.Elife2014;3:e01856 PMCID:PMC3896944

[46] Koizumi S,Hirayama S.The aspartyl protease DDI2 activates Nrf1 to compensate for proteasome dysfunction.Elife2016;5:e18357 PMCID:PMC5001836

[47] Tomlin FM,Liu YC.Inhibition of NGLY1 inactivates the transcription factor Nrf1 and potentiates proteasome inhibitor cytotoxicity.ACS Cent Sci2017;3:1143-55 PMCID:PMC5704294

[48] Chen T,Briere J.Multiple myeloma cells depend on the DDI2/NRF1-mediated proteasome stress response for survival.Blood Adv2021;bloodadvances.2020003820

[49] Kuhn DJ,Voorhees PM.Potent activity of carfilzomib, a novel, irreversible inhibitor of the ubiquitin-proteasome pathway, against preclinical models of multiple myeloma.Blood2007;110:3281-90 PMCID:PMC2200918

[50] Ghobrial IM,Siegel D.A phase Ib/II study of oprozomib in patients with advanced multiple myeloma and waldenström macroglobulinemia.Clin Cancer Res2019;25:4907-16

[51] Kumar SK,Niesvizky R.Safety and tolerability of ixazomib, an oral proteasome inhibitor, in combination with lenalidomide and dexamethasone in patients with previously untreated multiple myeloma: an open-label phase 1/2 study.Lancet Oncol2014;15:1503-12

[52] Chauhan D,Li G.A novel orally active proteasome inhibitor induces apoptosis in multiple myeloma cells with mechanisms distinct from Bortezomib.Cancer Cell2005;8:407-19

[53] Weyburne ES,Sha Z.Inhibition of the proteasome β2 site sensitizes triple-negative breast cancer cells to β5 inhibitors and suppresses Nrf1 activation.Cell Chem Biol2017;24:218-30 PMCID:PMC5341617

[54] Richardson PG,Hofmeister CC.Phase 1 study of marizomib in relapsed or relapsed and refractory multiple myeloma: NPI-0052-101 part 1.Blood2016;127:2693-700 PMCID:PMC5413296

[55] Crawford LJ.Targeting the ubiquitin proteasome system in haematological malignancies.Blood Rev2013;27:297-304

[56] Weathington NM.Emerging therapies targeting the ubiquitin proteasome system in cancer.J Clin Invest2014;124:6-12 PMCID:PMC3871250

[57] D'Arcy P,Olofsson MH.Inhibition of proteasome deubiquitinating activity as a new cancer therapy.Nat Med2011;17:1636-40

[58] Chauhan D,Nicholson B.A small molecule inhibitor of ubiquitin-specific protease-7 induces apoptosis in multiple myeloma cells and overcomes bortezomib resistance.Cancer Cell2012;22:345-58 PMCID:PMC3478134

[59] Besche HC,Kukushkin NV.Autoubiquitination of the 26S proteasome on Rpn13 regulates breakdown of ubiquitin conjugates.EMBO J2014;33:1159-76 PMCID:PMC4193922

[60] Song Y,Li S.Targeting proteasome ubiquitin receptor Rpn13 in multiple myeloma.Leukemia2016;30:1877-86 PMCID:PMC5749253

[61] Anchoori RK,Peng S.A bis-benzylidine piperidone targeting proteasome ubiquitin receptor RPN13/ADRM1 as a therapy for cancer.Cancer Cell2013;24:791-805 PMCID:PMC3881268

[62] Song Y,Wu L.Development and preclinical validation of a novel covalent ubiquitin receptor Rpn13 degrader in multiple myeloma.Leukemia2019;33:2685-94 PMCID:PMC6783320

[63] Rowinsky EK,Berdeja JG.Phase 1 study of the protein deubiquitinase inhibitor VLX1570 in patients with relapsed and/or refractory multiple myeloma.Invest New Drugs2020;38:1448-53 PMCID:PMC7497669

[64] Kategaya L,Rougé L.USP7 small-molecule inhibitors interfere with ubiquitin binding.Nature2017;550:534-8

[65] Turnbull AP,Krajewski WW.Molecular basis of USP7 inhibition by selective small-molecule inhibitors.Nature2017;550:481-6 PMCID:PMC6029662

[66] Ray A,Song Y.Blockade of deubiquitylating enzyme USP7 in plasmacytoid dendritic cells stimulates anti-myeloma immunity.Blood202;136:43

[67] Schauer NJ,Magin RS.Selective USP7 inhibition elicits cancer cell killing through a p53-dependent mechanism.Sci Rep2020;10:5324 PMCID:PMC7093416

[68] Ciechanover A,Varshavsky A.The ubiquitin-mediated proteolytic pathway and mechanisms of energy-dependent intracellular protein degradation.J Cell Biochem1984;24:27-53

[69] Hyer ML,Ciavarri J.A small-molecule inhibitor of the ubiquitin activating enzyme for cancer treatment.Nat Med2018;24:186-93

[70] Zhuang J,Singh RK.Ubiquitin-activating enzyme inhibition induces an unfolded protein response and overcomes drug resistance in myeloma.Blood2019;133:1572-84 PMCID:PMC6450433

[71] Buetow L.Structural insights into the catalysis and regulation of E3 ubiquitin ligases.Nat Rev Mol Cell Biol2016;17:626-42 PMCID:PMC6211636

[72] Enchev RI,Peter M.Protein neddylation: beyond cullin-RING ligases.Nat Rev Mol Cell Biol2015;16:30-44 PMCID:PMC5131867

[73] Mani A.The ubiquitin-proteasome pathway and its role in cancer.J Clin Oncol2005;23:4776-89

[74] Scheffner M,Huibregtse JM.Protein ubiquitination involving an E1-E2-E3 enzyme ubiquitin thioester cascade.Nature1995;373:81-3

[75] Zhu YX,Shi CX.Cereblon expression is required for the antimyeloma activity of lenalidomide and pomalidomide.Blood2011;118:4771-9 PMCID:PMC3208291

[76] Krönke J,Narla A.Lenalidomide causes selective degradation of IKZF1 and IKZF3 in multiple myeloma cells.Science2014;343:301-5 PMCID:PMC4077049

[77] Lu G,Sun H.The myeloma drug lenalidomide promotes the cereblon-dependent destruction of Ikaros proteins.Science2014;343:305-9 PMCID:PMC4070318

[78] McMillin DW,Delmore JE.Molecular and cellular effects of NEDD8-activating enzyme inhibition in myeloma.Mol Cancer Ther2012;11:942-51 PMCID:PMC3755358

[79] Shah JJ,O'Connor OA.Phase I study of the novel investigational NEDD8-activating enzyme inhibitor pevonedistat (MLN4924) in patients with relapsed/refractory multiple myeloma or lymphoma.Clin Cancer Res2016;22:34-43 PMCID:PMC5694347

[80] Kawaguchi Y,McLaurin A,Ito A.The deacetylase HDAC6 regulates aggresome formation and cell viability in response to misfolded protein stress.Cell2003;115:727-38

[81] Harada T,Anderson KC.Histone deacetylase inhibitors in multiple myeloma: from bench to bedside.Int J Hematol2016;104:300-9

[82] Catley L,Kiziltepe T.Aggresome induction by proteasome inhibitor bortezomib and alpha-tubulin hyperacetylation by tubulin deacetylase (TDAC) inhibitor LBH589 are synergistic in myeloma cells.Blood2006;108:3441-9 PMCID:PMC1895432

[83] Santo L,Kung AL.Preclinical activity, pharmacodynamic, and pharmacokinetic properties of a selective HDAC6 inhibitor, ACY-1215, in combination with bortezomib in multiple myeloma.Blood2012;119:2579-89 PMCID:PMC3337713

[84] San-miguel JF,Yoon S.Panobinostat plus bortezomib and dexamethasone versus placebo plus bortezomib and dexamethasone in patients with relapsed or relapsed and refractory multiple myeloma: a multicentre, randomised, double-blind phase 3 trial.Lancet Oncol2014;15:1195-206

[85] Dimopoulos M,Lonial S.Vorinostat or placebo in combination with bortezomib in patients with multiple myeloma (VANTAGE 088): a multicentre, randomised, double-blind study.Lancet Oncol2013;14:1129-40

[86] Yee AJ,Supko JG.Ricolinostat plus lenalidomide, and dexamethasone in relapsed or refractory multiple myeloma: a multicentre phase 1b trial.Lancet Oncol2016;17:1569-78

[87] Vogl DT,Jagannath S.Ricolinostat, the first selective histone deacetylase 6 inhibitor, in combination with bortezomib and dexamethasone for relapsed or refractory multiple myeloma.Clin Cancer Res2017;23:3307-15 PMCID:PMC5496796

[88] Ho M,Liu J.Targeting histone deacetylase 3 (HDAC3) in the bone marrow microenvironment inhibits multiple myeloma proliferation by modulating exosomes and IL-6 trans-signaling.Leukemia2020;34:196-209 PMCID:PMC6883144

[89] Levine B.Autophagy in the pathogenesis of disease.Cell2008;132:27-42 PMCID:PMC2696814

[90] Iwata A,Johnston JA.HDAC6 and microtubules are required for autophagic degradation of aggregated huntingtin.J Biol Chem2005;280:40282-92

[91] Hoang B,Shi Y,Lichtenstein A.Effect of autophagy on multiple myeloma cell viability.Mol Cancer Ther2009;8:1974-84

[92] Qiao L.Inhibition of lysosomal functions reduces proteasomal activity.Neurosci Lett2009;456:15-9

[93] Kawaguchi T,Moriya S.Combined treatment with bortezomib plus bafilomycin A1 enhances the cytocidal effect and induces endoplasmic reticulum stress in U266 myeloma cells: crosstalk among proteasome, autophagy-lysosome and ER stress.Int J Oncol2011;38:643-54

[94] Milan E,Cenci S.Autophagy in plasma cell ontogeny and malignancy.J Clin Immunol2016;36 Suppl 1:18-24 PMCID:PMC4891390

[95] Milan E,Resnati M.A plastic SQSTM1/p62-dependent autophagic reserve maintains proteostasis and determines proteasome inhibitor susceptibility in multiple myeloma cells.Autophagy2015;11:1161-78 PMCID:PMC4590585

[96] Ding WX,Gao W.Linking of autophagy to ubiquitin-proteasome system is important for the regulation of endoplasmic reticulum stress and cell viability.Am J Pathol2007;171:513-24 PMCID:PMC1934546

[97] Kouroku Y,Tanida I.ER stress (PERK/eIF2alpha phosphorylation) mediates the polyglutamine-induced LC3 conversion, an essential step for autophagy formation.Cell Death Differ2007;14:230-9

[98] Lu Y,Xu H,Jin F.Profilin 1 induces drug resistance through Beclin1 complex-mediated autophagy in multiple myeloma.Cancer Sci2018;109:2706-16 PMCID:PMC6125445

[99] Baranowska K,Starheim KK.Hydroxychloroquine potentiates carfilzomib toxicity towards myeloma cells.Oncotarget2016;7:70845-56 PMCID:PMC5342593

[100] Vogl DT,Tan KS.Combined autophagy and proteasome inhibition: a phase 1 trial of hydroxychloroquine and bortezomib in patients with relapsed/refractory myeloma.Autophagy2014;10:1380-90 PMCID:PMC4203515

[101] Woo CW,Arellano J.Adaptive suppression of the ATF4-CHOP branch of the unfolded protein response by toll-like receptor signalling.Nat Cell Biol2009;11:1473-80 PMCID:PMC2787632

[102] Sidrauski C.The transmembrane kinase Ire1p is a site-specific endonuclease that initiates mRNA splicing in the unfolded protein response.Cell1997;90:1031-9

[103] Carrasco DR,Protopopova M.The differentiation and stress response factor XBP-1 drives multiple myeloma pathogenesis.Cancer Cell2007;11:349-60 PMCID:PMC1885943

[104] Leung-Hagesteijn C,Cheung G.Xbp1s-negative tumor B cells and pre-plasmablasts mediate therapeutic proteasome inhibitor resistance in multiple myeloma.Cancer Cell2013;24:289-304 PMCID:PMC4118579

[105] Ali MM,Davenport EL.Structure of the Ire1 autophosphorylation complex and implications for the unfolded protein response.EMBO J2011;30:894-905 PMCID:PMC3049214

[106] Papandreou I,Olson M.Identification of an Ire1alpha endonuclease specific inhibitor with cytotoxic activity against human multiple myeloma.Blood2011;117:1311-4 PMCID:PMC3056474

[107] Mimura N,Gorgun G.Blockade of XBP1 splicing by inhibition of IRE1α is a promising therapeutic option in multiple myeloma.Blood2012;119:5772-81 PMCID:PMC3382937

[108] Bagratuni T,Mavrianou-Koutsoukou N.Characterization of a PERK kinase inhibitor with anti-myeloma activity.Cancers (Basel)2020;12:2864 PMCID:PMC7601861

[109] Kraus M,Overkleeft H.Nelfinavir augments proteasome inhibition by bortezomib in myeloma cells and overcomes bortezomib and carfilzomib resistance.Blood Cancer J2013;3:e103 PMCID:PMC3615215

[110] Besse A,Stolze SC.Nelfinavir blocks export of newly synthesized protein from the ER and interacts with ER-resident and mitochondrial proteins in an activity-dependent fashion.Blood2017;130:3074

[111] Driessen C,Joerger M.Treatment with the HIV protease inhibitor nelfinavir triggers the unfolded protein response and may overcome proteasome inhibitor resistance of multiple myeloma in combination with bortezomib: a phase I trial (SAKK 65/08).Haematologica2016;101:346-55 PMCID:PMC4815726

[112] Driessen C,Novak U.Promising activity of nelfinavir-bortezomib-dexamethasone in proteasome inhibitor-refractory multiple myeloma.Blood2018;132:2097-100 PMCID:PMC6238158

[113] Hebert DN,Molinari M.ERAD substrates: which way out?.Semin Cell Dev Biol2010;21:526-32

[114] Auner HW,Ward TH.Combined inhibition of p97 and the proteasome causes lethal disruption of the secretory apparatus in multiple myeloma cells.PLoS One2013;8:e74415 PMCID:PMC3775786

[115] Le Moigne R,Djakovic S.The p97 inhibitor CB-5083 is a unique disrupter of protein homeostasis in models of multiple myeloma.Mol Cancer Ther2017;16:2375-86

[116] Rasche L,Morgner C.The natural human IgM antibody PAT-SM6 induces apoptosis in primary human multiple myeloma cells by targeting heat shock protein GRP78.PLoS One2013;8:e63414 PMCID:PMC3646784

[117] Auner HW.Recent advances and future directions in targeting the secretory apparatus in multiple myeloma.Br J Haematol2015;168:14-25

[118] Lee AS.Glucose-regulated proteins in cancer: molecular mechanisms and therapeutic potential.Nat Rev Cancer2014;14:263-76 PMCID:PMC4158750

[119] Rasche L,Dubljevic V.A GRP78-directed monoclonal antibody recaptures response in refractory multiple myeloma with extramedullary involvement.Clin Cancer Res2016;22:4341-9

[120] Li Z.Heat-shock proteins.Curr Protoc Immunol2004;Appendix 1:Appendix 1T

[121] Agarraberes FA,Dice JF.An intralysosomal hsp70 is required for a selective pathway of lysosomal protein degradation.J Cell Biol1997;137:825-34 PMCID:PMC2139836

[122] Chiang HL,Plant CP.A role for a 70-kilodalton heat shock protein in lysosomal degradation of intracellular proteins.Science1989;246:382-5

[123] Wang B,Yu F.Hsp90 regulates autophagy and plays a role in cancer therapy.Tumour Biol2016;37:1-6

[124] Zhang L,Davies FE.Heat shock proteins in multiple myeloma.Oncotarget2014;5:1132-48 PMCID:PMC4012740

[125] Garcia-carbonero R,Paz-ares L.Inhibition of HSP90 molecular chaperones: moving into the clinic.Lancet Oncol2013;14:e358-69

[126] Bejarano E.Chaperone-mediated autophagy.Proc Am Thorac Soc2010;7:29-39 PMCID:PMC3137147

[127] Marcu MG,Bertolotti A,Hendershot L.Heat shock protein 90 modulates the unfolded protein response by stabilizing IRE1alpha.Mol Cell Biol2002;22:8506-13 PMCID:PMC139892

[128] Chatterjee M,Stühmer T.The PI3K/Akt signaling pathway regulates the expression of Hsp70, which critically contributes to Hsp90-chaperone function and tumor cell survival in multiple myeloma.Haematologica2013;98:1132-41 PMCID:PMC3696618

[129] Braunstein MJ,Scott CM.Antimyeloma effects of the heat shock protein 70 molecular chaperone inhibitor MAL3-101.J Oncol2011;2011:232037 PMCID:PMC3184436

[130] Ishii T,Nakashima T.Anti-tumor activity against multiple myeloma by combination of KW-2478, an Hsp90 inhibitor, with bortezomib.Blood Cancer J2012;2:e68 PMCID:PMC3346683

[131] Sydor JR,Pien CS.Development of 17-allylamino-17-demethoxygeldanamycin hydroquinone hydrochloride (IPI-504), an anti-cancer agent directed against Hsp90.Proc Natl Acad Sci U S A2006;103:17408-13 PMCID:PMC1635022

[132] Mimnaugh EG,Vos M.Simultaneous inhibition of hsp 90 and the proteasome promotes protein ubiquitination, causes endoplasmic reticulum-derived cytosolic vacuolization, and enhances antitumor activity.Mol Cancer Ther2004;3:551-66

[133] Lamottke B,Mieth M.The novel, orally bioavailable HSP90 inhibitor NVP-HSP990 induces cell cycle arrest and apoptosis in multiple myeloma cells and acts synergistically with melphalan by increased cleavage of caspases.Eur J Haematol2012;88:406-15

[134] Usmani SZ,Chiosis G.The anti-myeloma activity of a novel purine scaffold HSP90 inhibitor PU-H71 is via inhibition of both HSP90A and HSP90B1.J Hematol Oncol2010;3:40 PMCID:PMC2974653

[135] Stühmer T,Siegmund D.Signalling profile and antitumour activity of the novel Hsp90 inhibitor NVP-AUY922 in multiple myeloma.Leukemia2008;22:1604-12

[136] Bailey CK,Murphy ME.Efficacy of the HSP70 inhibitor PET-16 in multiple myeloma.Cancer Biol Ther2015;16:1422-6 PMCID:PMC4622955

[137] Seggewiss-Bernhardt R,Goh YT.Phase 1/1B trial of the heat shock protein 90 inhibitor NVP-AUY922 as monotherapy or in combination with bortezomib in patients with relapsed or refractory multiple myeloma.Cancer2015;121:2185-92

[138] Richardson PG,Alsina M.Tanespimycin monotherapy in relapsed multiple myeloma: results of a phase 1 dose-escalation study.Br J Haematol2010;150:438-45 PMCID:PMC3126095

[139] Siegel D,Vesole DH.A phase 1 study of IPI-504 (retaspimycin hydrochloride) in patients with relapsed or relapsed and refractory multiple myeloma.Leuk Lymphoma2011;52:2308-15

[140] Altun M,Shringarpure R.Effects of PS-341 on the activity and composition of proteasomes in multiple myeloma cells.Cancer Res2005;65:7896-901

[141] Jain S,Zain J.Emerging role of carfilzomib in treatment of relapsed and refractory lymphoid neoplasms and multiple myeloma.Core Evid2011;6:43-57 PMCID:PMC3102580

[142] Nawrocki ST,Maclean KH.Myc regulates aggresome formation, the induction of Noxa, and apoptosis in response to the combination of bortezomib and SAHA.Blood2008;112:2917-26 PMCID:PMC2556625

[143] Zhang L,Mirabella F.Hsp70 inhibition induces myeloma cell death via the intracellular accumulation of immunoglobulin and the generation of proteotoxic stress.Cancer Lett2013;339:49-59 PMCID:PMC3778988

[144] Fok JHL,Zhang L.HSF1 is essential for myeloma cell survival and a promising therapeutic target.Clin Cancer Res2018;24:2395-407 PMCID:PMC6420136

[145] Tian Z,Wang X.A novel small molecule inhibitor of deubiquitylating enzyme USP14 and UCHL5 induces apoptosis in multiple myeloma and overcomes bortezomib resistance.Blood2014;123:706-16 PMCID:PMC3907756

[146] Shanmugam M,Qian J.Targeting glucose consumption and autophagy in myeloma with the novel nucleoside analogue 8-aminoadenosine.J Biol Chem2009;284:26816-30 PMCID:PMC2785370

[147] Holstein SA.Isoprenoid biosynthetic pathway inhibition disrupts monoclonal protein secretion and induces the unfolded protein response pathway in multiple myeloma cells.Leuk Res2011;35:551-9 PMCID:PMC3038195

[148] Cross BC,Sadowski PG.The molecular basis for selective inhibition of unconventional mRNA splicing by an IRE1-binding small molecule.Proc Natl Acad Sci U S A2012;109:E869-78 PMCID:PMC3326519

[149] Goloudina AR,Garrido C.Inhibition of HSP70: a challenging anti-cancer strategy.Cancer Lett2012;325:117-24

[150] Atkins C,Minthorn E.Characterization of a novel PERK kinase inhibitor with antitumor and antiangiogenic activity.Cancer Res2013;73:1993-2002

[151] Stühmer T,Grella E.Anti-myeloma activity of the novel 2-aminothienopyrimidine Hsp90 inhibitor NVP-BEP800.Br J Haematol2009;147:319-27

[152] Okawa Y,Steed P.SNX-2112, a selective Hsp90 inhibitor, potently inhibits tumor cell growth, angiogenesis, and osteoclastogenesis in multiple myeloma and other hematologic tumors by abrogating signaling via Akt and ERK.Blood2009;113:846-55 PMCID:PMC2630270

[153] Suzuki R,Mimura N.Anti-tumor activities of selective HSP90α/β inhibitor, TAS-116, in combination with bortezomib in multiple myeloma.Leukemia2015;29:510-4 PMCID:PMC4318711

[154] Winter GE,Paulk J.DRUG DEVELOPMENT. Phthalimide conjugation as a strategy for in vivo target protein degradation.Science2015;348:1376-81 PMCID:PMC4937790