MYC inhibitors in multiple myeloma

Abstract

The importance of MYC function in cancer was discovered in the late 1970s when the sequence of the avian retrovirus that causes myelocytic leukemia was identified. Since then, over 40 years of unceasing research have highlighted the significance of this protein in malignant transformation, especially in hematologic diseases. Indeed, some of the earliest connections among the higher expression of proto-oncogenes (such as MYC), genetic rearrangements and their relation to cancer development were made in Burkitt lymphoma, chronic myeloid leukemia and mouse plasmacytomas. Multiple myeloma (MM), in particular, is a plasma cell malignancy strictly associated with MYC deregulation, suggesting that therapeutic strategies against it would be beneficial in treating this disease. However, targeting MYC was - and, somehow, still is - challenging due to its unique properties: lack of defined three-dimensional structure, nuclear localization and absence of a targetable enzymatic pocket. Despite these difficulties, however, many studies have shown the potential therapeutic impact of direct or indirect MYC inhibition. Different molecules have been tested, in fact, in the context of MM. In this review, we summarize the current status of the different compounds, including the results of their clinical testing, and propose to continue with the efforts to identify, repurpose, redesign or improve drug candidates to combine them with standard of care therapies to overcome resistance and enable better management of myeloma treatment.

Keywords

MYC inhibition / multiple myeloma / undruggable target / targeted therapies / transcription factor / epigenetics / MYC downregulation

References

[1] Kazandjian D.Multiple myeloma epidemiology and survival: A unique malignancy.Semin Oncol2016;43:676-81 PMCID:PMC5283695

[2] GLOBOCAN. Cancer Today. Estimated number of new cases in 2020, WHO Europe (EURO), both sexes, all ages. Available from: https://gco.iarc.fr/today/online-analysis-table?v=2020&mode=cancer&mode_population=continents&population-=900&populations=994&key=asr&sex=0&cancer=39&type=0&statistic=5&prevalence=0&population_group=0&ages_group%5B%5D=0&ages_group%5B%5D=17&group_cancer=0&include_nmsc=1&include_nmsc_other=1. [Last accessed on 19 Aug 2021]

[3] GLOBOCAN. Cancer Today. Estimated number of new cases in 2020, worldwide, both sexes, all ages. Available from: https://gco.iarc.fr/today/online-analysis-table?v=2020&mode=cancer&mode_population=continents&population-=900&populations=900&key=asr&sex=0&cancer=39&type=0&statistic=5&prevalence=0&population_group=0&ages_group%5B%5D=0&ages_group%5B%5D=17&group_cancer=0&include_nmsc=1&include_nmsc_other=1. [Last accessed on 19 Aug 2021]

[4] Kumar SK,Kyle RA.Multiple myeloma.Nat Rev Dis Primers2017;3:17046

[5] de la Puente P.Nanoparticle delivery systems, general approaches, and their implementation in multiple myeloma.Eur J Haematol2017;98:529-41 PMCID:PMC5438273

[6] Kurtin SE.Relapsed or relapsed/refractory multiple myeloma.J Adv Pract Oncol2013;4:5-14

[7] Ravi P,Cerhan JR.Defining cure in multiple myeloma: a comparative study of outcomes of young individuals with myeloma and curable hematologic malignancies.Blood Cancer J2018;8:26 PMCID:PMC5849889

[8] Cancer Research UK, Myeloma incidence statistics 2016. Available from: https://www.cancerresearchuk.org/health-professional/cancer-statistics/statistics-by-cancer-type/myeloma/incidence. [Last accessed on 19 Aug 2021]

[9] GLOBOCAN. Cancer Tomorrow. Estimated number of new cases from 2020 to 2040, Both sexes, age [0-85+] Multiple myeloma and immunoproliferative diseases World. Available from: https://gco.iarc.fr/tomorrow/en/dataviz/isotype?cancers=35&single_unit=50000&years=2040&group_populations=0&multiple_populations=0&group_cancers=0&multiple_cancers=0. [Last accessed on 19 Aug 2021]

[10] Manier S,Park J,Getz G.Genomic complexity of multiple myeloma and its clinical implications.Nat Rev Clin Oncol2017;14:100-13

[11] Landgren O,Pfeiffer RM.Monoclonal gammopathy of undetermined significance (MGUS) consistently precedes multiple myeloma: a prospective study.Blood2009;113:5412-7 PMCID:PMC2689042

[12] Kyle RA,Rajkumar SV.A long-term study of prognosis in monoclonal gammopathy of undetermined significance.N Engl J Med2002;346:564-9

[13] Kyle RA,Therneau TM.Clinical course and prognosis of smoldering (asymptomatic) multiple myeloma.N Engl J Med2007;356:2582-90

[14] Kovalchuk AL,Janz S.Clonal diversification of primary BALB/c plasmacytomas harboring T(12;15) chromosomal translocations.Leukemia2000;14:909-21

[15] Walker BA,Wardell CP.Identification of novel mutational drivers reveals oncogene dependencies in multiple myeloma.Blood2018;132:587-97 PMCID:PMC6097138

[16] Jovanović KK,Ghobrial IM,Quesnel B.Targeting MYC in multiple myeloma.Leukemia2018;32:1295-306

[17] Dib A,Glebov OK,Kuehl WM.Characterization of MYC translocations in multiple myeloma cell lines.J Natl Cancer Inst Monogr2008;25-31 PMCID:PMC2737184

[18] Weinhold N,Rasche L.Clonal selection and double-hit events involving tumor suppressor genes underlie relapse in myeloma.Blood2016;128:1735-44 PMCID:PMC5043128

[19] Terpos E,Gavriatopoulou M.Pathogenesis of bone disease in multiple myeloma: from bench to bedside.Blood Cancer J2018;8:7 PMCID:PMC5802524

[20] Garcia-Gomez A,Del Cañizo MC,Garayoa M.Multiple myeloma mesenchymal stromal cells: contribution to myeloma bone disease and therapeutics.World J Stem Cells2014;6:322-43 PMCID:PMC4131274

[21] Higgs JT,Wang H.Mesenchymal stem cells expressing osteoprotegerin variants inhibit osteolysis in a murine model of multiple myeloma.Blood Adv2017;1:2375-85 PMCID:PMC5729616

[22] Chae YK,Davis AA.Path toward precision oncology: review of targeted therapy studies and tools to aid in defining "actionability" of a molecular lesion and patient management support.Mol Cancer Ther2017;16:2645-55

[23] Badalian-Very G.Personalized medicine in hematology - a landmark from bench to bed.Comput Struct Biotechnol J2014;10:70-7 PMCID:PMC4204427

[24] Schwartzberg L,Liu D.Precision oncology: who, how, what, when, and when not?.Am Soc Clin Oncol Educ Book2017;37:160-9

[25] Shin SH,Dong Z.Precision medicine: the foundation of future cancer therapeutics.NPJ Precis Oncol2017;1:12 PMCID:PMC5871793

[26] Hantschel O,Superti-Furga G.Target spectrum of the BCR-ABL inhibitors imatinib, nilotinib and dasatinib.Leuk Lymphoma2008;49:615-9

[27] Bhullar KS,McGowan EM.Kinase-targeted cancer therapies: progress, challenges and future directions.Mol Cancer2018;17:48 PMCID:PMC5817855

[28] NIH NCI. Targeted cancer therapies. Available from: https://www.cancer.gov/about-cancer/treatment/types/targeted-therapies/targeted-therapies-fact-sheet#what-targeted-therapies-have-been-approved-for-specific-types-of-cancer. [Last accessed on 19 Aug 2021]

[29] Rossi JF.Targeted therapies in adult B-cell malignancies.Biomed Res Int2015;2015:217593 PMCID:PMC4575712

[30] Fabbro D,Moebitz H.Ten things you should know about protein kinases: IUPHAR Review 14.Br J Pharmacol2015;172:2675-700 PMCID:PMC4439867

[31] Balik K,Maj M,Bajek A.Limitations of molecularly targeted therapy.Medical Research Journal2019;4:99-105

[32] Wallington-Beddoe CT,Kuss BJ.Resistance to proteasome inhibitors and other targeted therapies in myeloma.Br J Haematol2018;182:11-28

[33] Sabnis AJ.Principles of resistance to targeted cancer therapy: lessons from basic and translational cancer biology.Trends Mol Med2019;25:185-97 PMCID:PMC6401263

[34] Hann SR.MYC cofactors: molecular switches controlling diverse biological outcomes.Cold Spring Harb Perspect Med2014;4:a014399 PMCID:PMC4143105

[35] Barrett J,Kato GJ,Dang CV.Activation domains of L-Myc and c-Myc determine their transforming potencies in rat embryo cells.Mol Cell Biol1992;12:3130-7 PMCID:PMC364527

[36] Nesbit CE,Yin X.Differential apoptotic behaviors of c-myc, N-myc, and L-myc oncoproteins.Cell Growth Differ1998;9:731-41

[37] Dang CV.MYC on the path to cancer.Cell2012;149:22-35 PMCID:PMC3345192

[38] Stefan E. MYC and RAF: key effectors in cellular signaling and major drivers in human cancer. In: Hunter E, Bister K, editors. Viruses, genes, and cancer. Cham: Springer International Publishing; 2017. p. 117-51.

[39] Nasi S,Jucker R,Soucek L.Making decisions through Myc.FEBS Letters2001;490:153-62

[40] Soucek L.The ups and downs of Myc biology.Curr Opin Genet Dev2010;20:91-5 PMCID:PMC2822095

[41] Conacci-Sorrell M,Eisenman RN.An overview of MYC and its interactome.Cold Spring Harb Perspect Med2014;4:a014357 PMCID:PMC3869278

[42] Stine ZE,Altman BJ,Dang CV.MYC, metabolism, and cancer.Cancer Discov2015;5:1024-39 PMCID:PMC4592441

[43] Davis AC,Spotts GD,Bradley A.A null c-myc mutation causes lethality before 10.5 days of gestation in homozygotes and reduced fertility in heterozygous female mice.Genes Dev1993;7:671-82

[44] Schaub FX,Berger AC.Cancer Genome Atlas NetworkPan-cancer alterations of the MYC oncogene and its proximal network across the cancer genome atlas.Cell Syst2018;6:282-300.e2 PMCID:PMC5892207

[45] Gabay M,Felsher DW.MYC activation is a hallmark of cancer initiation and maintenance.Cold Spring Harb Perspect Med2014;4:a014241 PMCID:PMC4031954

[46] Dhillon P.In conversation with Gerard Evan.FEBS J2019;286:4824-31

[47] Dominguez-Sola D.MYC and the control of DNA replication.Cold Spring Harb Perspect Med2014;4:a014423 PMCID:PMC4031955

[48] Sabò A.Genome recognition by MYC.Cold Spring Harb Perspect Med2014;4:a014191 PMCID:PMC3904094

[49] Hanahan D.Hallmarks of cancer: the next generation.Cell2011;144:646-74

[50] Tannock I,Bristow R. The basic science of oncology. 5th ed: McGraw-Hill Professional; 2013. p. 588.

[51] Holien T,Olsen OE.MYC amplifications in myeloma cell lines: correlation with MYC-inhibitor efficacy.Oncotarget2015;6:22698-705 PMCID:PMC4673192

[52] Felsher DW.Reversible tumorigenesis by MYC in hematopoietic lineages.Molecular Cell1999;4:199-207

[53] Pelengaris S,Khan M,Evan G.Reversible activation of c-Myc in skin.Molecular Cell1999;3:565-77

[54] Giuriato S,Fan AC,Felsher DW.Conditional animal models: a strategy to define when oncogenes will be effective targets to treat cancer.Semin Cancer Biol2004;14:3-11

[55] Arvanitis C.Conditionally MYC: insights from novel transgenic models.Cancer Lett2005;226:95-9

[56] Jain M,Chu K.Sustained loss of a neoplastic phenotype by brief inactivation of MYC.Science2002;297:102-4

[57] Pelengaris S,Evan GI.Suppression of Myc-induced apoptosis in β cells exposes multiple oncogenic properties of Myc and triggers carcinogenic progression.Cell2002;109:321-34

[58] Marinkovic D,Mahr B,Wirth T.Reversible lymphomagenesis in conditionally c-MYC expressing mice.Int J Cancer2004;110:336-42

[59] Soucek L,Martins CP.Modelling Myc inhibition as a cancer therapy.Nature2008;455:679-83 PMCID:PMC4485609

[60] Soucek L,Sodir NM.Inhibition of Myc family proteins eradicates KRas-driven lung cancer in mice.Genes Dev2013;27:504-13 PMCID:PMC3605464

[61] Dang CV,Shokat KM.Drugging the 'undruggable' cancer targets.Nat Rev Cancer2017;17:502-8 PMCID:PMC5945194

[62] Whitfield JR,Soucek L.Strategies to inhibit Myc and their clinical applicability.Front Cell Dev Biol2017;5:10 PMCID:PMC5322154

[63] Soucek L,Panacchia L,Tatò F.Omomyc, a potential Myc dominant negative, enhances Myc-induced apoptosis.Cancer Res2002;62:3507-10

[64] Savino M,Carucci N.The action mechanism of the Myc inhibitor termed Omomyc may give clues on how to target Myc for cancer therapy.PLoS One2011;6:e22284 PMCID:PMC3141027

[65] Massó-Vallés D.Blocking Myc to treat cancer: reflecting on two decades of Omomyc.Cells2020;9:883 PMCID:PMC7226798

[66] Koh CM,Guccione E.Targeting MYC in cancer therapy: RNA processing offers new opportunities.Bioessays2016;38:266-75 PMCID:PMC4819695

[67] Gu J,Han H.The BET bromodomain inhibitor OTX015 synergizes with targeted agents in multiple myeloma.Mol Pharm2018;15:5387-96

[68] Díaz T,Lozano E.The BET bromodomain inhibitor CPI203 improves lenalidomide and dexamethasone activity in in vitro and in vivo models of multiple myeloma by blockade of Ikaros and MYC signaling.Haematologica2017;102:1776-84 PMCID:PMC5622862

[69] Lim SL,Han BC,Chng WJ.Multiple myeloma: Combination therapy of BET proteolysis targeting chimeric molecule with CDK9 inhibitor.PLoS One2020;15:e0232068 PMCID:PMC7304913

[70] Stubbs MC,Sparks R.The novel bromodomain and extraterminal domain inhibitor INCB054329 induces vulnerabilities in myeloma cells that inform rational combination strategies.Clin Cancer Res2019;25:300-11

[71] Falchook G,LoRusso P.Development of 2 bromodomain and extraterminal inhibitors with distinct pharmacokinetic and pharmacodynamic profiles for the treatment of advanced malignancies.Clin Cancer Res2020;26:1247-57 PMCID:PMC7528620

[72] Shapiro GI,Dowlati A.A Phase 1 study of RO6870810, a novel bromodomain and extra-terminal protein inhibitor, in patients with NUT carcinoma, other solid tumours, or diffuse large B-cell lymphoma.Br J Cancer2021;124:744-53 PMCID:PMC7884382

[73] Ishiguro K,Niinuma T.DOT1L inhibition blocks multiple myeloma cell proliferation by suppressing IRF4-MYC signaling.Haematologica2019;104:155-65 PMCID:PMC6312027

[74] Yap TA,Giulino-Roth L.Phase I study of the novel enhancer of zeste homolog 2 (EZH2) inhibitor GSK2816126 in patients with advanced hematologic and solid tumors.Clin Cancer Res2019;25:7331-9 PMCID:PMC7377921

[75] Dafflon C,Barys L.DOT1L inhibition is lethal for multiple myeloma due to perturbation of the endoplasmic reticulum stress pathway.Oncotarget2020;11:956-68 PMCID:PMC7082114

[76] Tang S,Cheng B.Crucial role of HO-1/IRF4-dependent apoptosis induced by panobinostat and lenalidomide in multiple myeloma.Exp Cell Res2018;363:196-207

[77] Laubach JP,Rosenblatt JM.Phase 1 open-label study of panobinostat, lenalidomide, bortezomib + dexamethasone in relapsed and relapsed/refractory multiple myeloma.Blood Cancer J2021;11:20 PMCID:PMC7873303

[78] Mondala PK,Zhou T.Selective antisense oligonucleotide inhibition of human IRF4 prevents malignant myeloma regeneration via cell cycle disruption.Cell Stem Cell2021;28:623-36.e9 PMCID:PMC8026723

[79] Das DS,Das A.A novel hypoxia-selective epigenetic agent RRx-001 triggers apoptosis and overcomes drug resistance in multiple myeloma cells.Leukemia2016;30:2187-97 PMCID:PMC5093055

[80] Cabrales P,Oronsky B.Rrx-001 is a phase 3 small molecule dual inhibitor of CD47 and Sirpα with activity in multiple myeloma.Blood2018;132:5623

[81] Zhang Y,Bandyopadhyay D.The covalent CDK7 inhibitor THZ1 potently induces apoptosis in multiple myeloma cells in vitro and in vivo.Clin Cancer Res2019;25:6195-205 PMCID:PMC6801078

[82] Czudor Z,Bánhegyi P.Novel compounds with potent CDK9 inhibitory activity for the treatment of myeloma.Bioorg Med Chem Lett2018;28:769-73

[83] Hu S,Rajagopal N.Discovery and characterization of SY-1365, a selective, covalent inhibitor of CDK7.Cancer Res2019;79:3479-91

[84] Cidado J,Proia T.AZD4573 is a highly selective CDK9 inhibitor that suppresses MCL-1 and induces apoptosis in hematologic cancer cells.Clin Cancer Res2020;26:922-34

[85] Sun K,Borek MA.Dual HDAC and PI3K inhibitor CUDC-907 downregulates MYC and suppresses growth of MYC-dependent cancers.Mol Cancer Ther2017;16:285-99

[86] Paíno T,González-Méndez L.The novel pan-PIM kinase inhibitor, PIM447, displays dual antimyeloma and bone-protective effects, and potently synergizes with current standards of care.Clin Cancer Res2017;23:225-38

[87] Paíno T,San-Segundo L.Protein translation inhibition is involved in the activity of the pan-PIM kinase inhibitor PIM447 in combination with pomalidomide-dexamethasone in multiple myeloma.Cancers (Basel)2020;12:2743 PMCID:PMC7598606

[88] Raab MS,Ocio EM.The first-in-human study of the pan-PIM kinase inhibitor PIM447 in patients with relapsed and/or refractory multiple myeloma.Leukemia2019;33:2924-33

[89] Buettner R,Caserta E.Leflunomide regulates c-Myc expression in myeloma cells through PIM targeting.Blood Adv2019;3:1027-32 PMCID:PMC6457239

[90] Rosenzweig M,Tsai NC.Repurposing leflunomide for relapsed/refractory multiple myeloma: a phase 1 study.Leuk Lymphoma2020;61:1669-77 PMCID:PMC7384948

[91] Vogl DT,Cornell RF.Selective inhibition of nuclear export with oral selinexor for treatment of relapsed or refractory multiple myeloma.J Clin Oncol2018;36:859-66 PMCID:PMC6905485

[92] Chari A,Gavriatopoulou M.Oral Selinexor-dexamethasone for triple-class refractory multiple myeloma.N Engl J Med2019;381:727-38

[93] Mateos MV,Facon T.Effect of prior treatments on selinexor, bortezomib, and dexamethasone in previously treated multiple myeloma.J Hematol Oncol2021;14:59 PMCID:PMC8045319

[94] Richard S,Delimpasi S.Selinexor, bortezomib, and dexamethasone versus bortezomib and dexamethasone in previously treated multiple myeloma: Outcomes by cytogenetic risk.Am J Hematol2021;96:1120-30

[95] Auner HW,Delimpasi S.Effect of age and frailty on the efficacy and tolerability of once-weekly selinexor, bortezomib, and dexamethasone in previously treated multiple myeloma.Am J Hematol2021;96:708-18

[96] Grosicki S,Spicka I.Once-per-week selinexor, bortezomib, and dexamethasone versus twice-per-week bortezomib and dexamethasone in patients with multiple myeloma (BOSTON): a randomised, open-label, phase 3 trial.Lancet2020;396:1563-73

[97] Itoua Maïga R,Chu J.Oxo-aglaiastatin-mediated inhibition of translation initiation.Sci Rep2019;9:1265 PMCID:PMC6361980

[98] Grieve S,Lees M.TAZ functions as a tumor suppressor in multiple myeloma by downregulating MYC.Blood Adv2019;3:3613-25 PMCID:PMC6880893

[99] Ronca R,Maccarinelli F.FGF trapping inhibits multiple myeloma growth through c-Myc degradation-induced mitochondrial oxidative stress.Cancer Res2020;80:2340-54

[100] Chae YK,Vaklavas C.Phase II Study of AZD4547 in patients with tumors harboring aberrations in the FGFR pathway: results from the NCI-MATCH trial (EAY131) subprotocol W.J Clin Oncol2020;38:2407-17 PMCID:PMC7367548

[101] Yao R,Sun X.Identification of a novel c-Myc inhibitor 7594-0037 by structure-based virtual screening and investigation of its anti-cancer effect on multiple myeloma.Drug Des Devel Ther2020;14:3983-93 PMCID:PMC7532311

[102] Cao Y,Liu M.Directly targeting c-Myc contributes to the anti-multiple myeloma effect of anlotinib.Cell Death Dis2021;12:396 PMCID:PMC8046985

[103] Shen G,Ren D.Anlotinib: a novel multi-targeting tyrosine kinase inhibitor in clinical development.J Hematol Oncol2018;11:120 PMCID:PMC6146601

[104] Simmons JK,Gamache BJ.Cooperative targets of combined mTOR/HDAC inhibition promote MYC degradation.Mol Cancer Ther2017;16:2008-21 PMCID:PMC5587368

[105] Delmore JE,Lemieux ME.BET bromodomain inhibition as a therapeutic strategy to target c-Myc.Cell2011;146:904-17 PMCID:PMC3187920

[106] Shi J,Han H.Potent activity of the bromodomain inhibitor OTX015 in multiple myeloma.Mol Pharm2018;15:4139-47

[107] Lin X,Uziel T.HEXIM1 as a robust pharmacodynamic marker for monitoring target engagement of BET family bromodomain inhibitors in tumors and surrogate tissues.Mol Cancer Ther2017;16:388-96

[108] Cochran AG,Sims RJ 3rd.Bromodomains: a new target class for drug development.Nat Rev Drug Discov2019;18:609-28

[109] Stathis A.BET proteins as targets for anticancer treatment.Cancer Discov2018;8:24-36

[110] Alqahtani A,Ashraf M.Bromodomain and extra-terminal motif inhibitors: a review of preclinical and clinical advances in cancer therapy.Future Sci OA2019;5:FSO372 PMCID:PMC6426170

[111] Genta S,Stathis A.BET and EZH2 inhibitors: novel approaches for targeting cancer.Curr Oncol Rep2019;21:13

[112] Sun Y,Wang Z,Sun Y.Safety and efficacy of bromodomain and extra-terminal inhibitors for the treatment of hematological malignancies and solid tumors: a systematic study of clinical trials.Front Pharmacol2020;11:621093 PMCID:PMC7870522

[113] Cheng Y,Wang M.Targeting epigenetic regulators for cancer therapy: mechanisms and advances in clinical trials.Signal Transduct Target Ther2019;4:62 PMCID:PMC6915746

[114] Tu WB,Lourenco C.MYC Interacts with the G9a histone methyltransferase to drive transcriptional repression and tumorigenesis.Cancer Cell2018;34:579-95.e8

[115] Tremblay-LeMay R,Pourabdollah M.EZH2 as a therapeutic target for multiple myeloma and other haematological malignancies.Biomark Res2018;6:34 PMCID:PMC6286605

[116] Vatapalli R,Rodriguez Y.Histone methyltransferase DOT1L coordinates AR and MYC stability in prostate cancer.Nat Commun2020;11:4153 PMCID:PMC7438336

[117] Ishiguro K,Niinuma T.Dual EZH2 and G9a inhibition suppresses multiple myeloma cell proliferation by regulating the interferon signal and IRF4-MYC axis.Cell Death Discov2021;7:7 PMCID:PMC7803977

[118] Oronsky B,Oronsky A,Carter CA.Brief report: RRx-001 is a c-Myc inhibitor that targets cancer stem cells.Oncotarget2018;9:23439-42 PMCID:PMC5955127

[119] Caroen S,Carter C,Oronsky A.Rationale and necessity for delivery of RRx-001, a Myc and CD47 antagonist, by intravenous blood mix.Expert Opin Drug Deliv2020;17:741-2

[120] Oronsky B,Caroen S,Oronsky A.RRx-001, a first-in-class small molecule inhibitor of MYC and a downregulator of CD47, is an "erythrophagoimmunotherapeutic".Oncoimmunology2020;9:1746172 PMCID:PMC7790525

[121] Stein EM,Rizzieri DA.The DOT1L inhibitor pinometostat reduces H3K79 methylation and has modest clinical activity in adult acute leukemia.Blood2018;131:2661-9 PMCID:PMC6265654

[122] Kelso TW,Eickhoff J.Cyclin-dependent kinase 7 controls mRNA synthesis by affecting stability of preinitiation complexes, leading to altered gene expression, cell cycle progression, and survival of tumor cells.Mol Cell Biol2014;34:3675-88 PMCID:PMC4187722

[123] Chipumuro E,Christensen CL.CDK7 inhibition suppresses super-enhancer-linked oncogenic transcription in MYCN-driven cancer.Cell2014;159:1126-39 PMCID:PMC4243043

[124] Kwiatkowski N,Rahl PB.Targeting transcription regulation in cancer with a covalent CDK7 inhibitor.Nature2014;511:616-20 PMCID:PMC4244910

[125] Chesler L,Goldenberg DD.Inhibition of phosphatidylinositol 3-kinase destabilizes Mycn protein and blocks malignant progression in neuroblastoma.Cancer Res2006;66:8139-46 PMCID:PMC2924674

[126] Roohi A.Recent advances in targeting mTOR signaling pathway using small molecule inhibitors.J Drug Target2017;25:189-201

[127] Pei Y,Wang J.HDAC and PI3K antagonists cooperate to inhibit growth of MYC-driven medulloblastoma.Cancer Cell2016;29:311-23 PMCID:PMC4794752

[128] Chiu H,Jackson LV.Reduced eIF4E function impairs B-cell leukemia without altering normal B-lymphocyte function.iScience2021;24:102748 PMCID:PMC8261676

[129] Mougiakakos D,Böttcher M.The IKZF1-IRF4/IRF5 axis controls polarization of myeloma-associated macrophages.Cancer Immunol Res2021;9:265-78

[130] Pal I,Jovanovic M,Deng C.Targeting translation of mRNA as a therapeutic strategy in cancer.Curr Hematol Malig Rep2019;14:219-27

[131] Taroncher-Oldenburg G,Obermann W,Hartmann RK.Targeting the DEAD-Box RNA helicase eIF4A with Rocaglates-A pan-antiviral strategy for minimizing the impact of future RNA virus pandemics.Microorganisms2021;9:540 PMCID:PMC8001013

[132] Sun XX,Yin L,Sears RC.The nucleolar ubiquitin-specific protease USP36 deubiquitinates and stabilizes c-Myc.Proc Natl Acad Sci U S A2015;112:3734-9 PMCID:PMC4378440

[133] Huang HL,Wang LQ.Triggering Fbw7-mediated proteasomal degradation of c-Myc by oridonin induces cell growth inhibition and apoptosis.Mol Cancer Ther2012;11:1155-65

[134] Yang D.Structure of the biologically relevant G-quadruplex in the c-MYC promoter.Nucleosides Nucleotides Nucleic Acids2006;25:951-68

[135] Brooks TA.Targeting MYC Expression through G-Quadruplexes.Genes Cancer2010;1:641-9 PMCID:PMC2992328

[136] Brown RV,Gokhale V,Brooks TA.Demonstration that drug-targeted down-regulation of MYC in non-Hodgkins lymphoma is directly mediated through the promoter G-quadruplex.J Biol Chem2011;286:41018-27 PMCID:PMC3220475

[137] Ferreira R,Panov KI,Hannan RD.Targeting the RNA polymerase I transcription for cancer therapy comes of age.Cells2020;9:266 PMCID:PMC7072222

[138] Khot A,Cameron DP.First-in-human RNA polymerase I transcription inhibitor CX-5461 in patients with advanced hematologic cancers: results of a phase I dose-escalation study.Cancer Discov2019;9:1036-49

[139] Leung AWY,Dragowska WH,Bally MB.Copper-CX-5461: A novel liposomal formulation for a small molecule rRNA synthesis inhibitor.J Control Release2018;286:1-9

[140] Calabrese DR,Leon EC.Chemical and structural studies provide a mechanistic basis for recognition of the MYC G-quadruplex.Nat Commun2018;9:4229 PMCID:PMC6185959

[141] Gaikwad SM,Arteaga AQ.A small molecule stabilizer of the MYC G4-quadruplex induces endoplasmic reticulum stress, senescence and pyroptosis in multiple myeloma.Cancers (Basel)2020;12:2952 PMCID:PMC7650714

[142] Minard A,Raguseo F.A short peptide that preferentially binds c-MYC G-quadruplex DNA.Chem Commun (Camb)2020;56:8940-3

[143] Webb MS,Cremese M.Toxicity and toxicokinetics of a phosphorothioate oligonucleotide against the c-myc oncogene in cynomolgus monkeys.Antisense Nucleic Acid Drug Dev2001;11:155-63

[144] Arora V,Smith BL.c-Myc antisense limits rat liver regeneration and indicates role for c-Myc in regulating cytochrome P-450 3A activity.J Pharmacol Exp Ther2000;292:921-8

[145] Wang H,Grachtchouk V.c-Myc depletion inhibits proliferation of human tumor cells at various stages of the cell cycle.Oncogene2008;27:1905-15 PMCID:PMC3144565

[146] Tolcher AW,Patnaik A.Safety and activity of DCR-MYC, a first-in-class Dicer-substrate small interfering RNA (DsiRNA) targeting MYC, in a phase I study in patients with advanced solid tumors.JCO2015;33:11006

[147] Morelli E,Federico C.Therapeutic vulnerability of multiple myeloma to MIR17PTi, a first-in-class inhibitor of pri-miR-17-92.Blood2018;132:1050-63 PMCID:PMC6128086

[148] Caracciolo D,Juli G.Exploiting MYC-induced PARPness to target genomic instability in multiple myeloma.Haematologica2021;106:185-95 PMCID:PMC7776341

[149] Sorolla A,Golden E.Precision medicine by designer interference peptides: applications in oncology and molecular therapeutics.Oncogene2020;39:1167-84 PMCID:PMC7002299

[150] Berg T,Desharnais J.Small-molecule antagonists of Myc/Max dimerization inhibit Myc-induced transformation of chicken embryo fibroblasts.Proc Natl Acad Sci U S A2002;99:3830-5 PMCID:PMC122609

[151] Yin X,Lazo JS.Low molecular weight inhibitors of Myc-Max interaction and function.Oncogene2003;22:6151-9

[152] Fletcher S.Small-molecule inhibitors of the Myc oncoprotein.Biochim Biophys Acta2015;1849:525-43 PMCID:PMC4169356

[153] Kiessling A,Sperl B.Selective inhibition of c-Myc/Max dimerization by a pyrazolo[1,5-a]pyrimidine.ChemMedChem2007;2:627-30

[154] Hart JR,Yu J.Inhibitor of MYC identified in a Kröhnke pyridine library.Proc Natl Acad Sci U S A2014;111:12556-61 PMCID:PMC4151726

[155] Mo H.Identification of small molecules that induce apoptosis in a Myc-dependent manner and inhibit Myc-driven transformation.Proc Natl Acad Sci U S A2006;103:6344-9 PMCID:PMC1435363

[156] Jeong KC,Seo HH.Intravesical instillation of c-MYC inhibitor KSI-3716 suppresses orthotopic bladder tumor growth.J Urol2014;191:510-8

[157] Giorello L,Pescarolo MP.Inhibition of cancer cell growth and c-Myc transcriptional activity by a c-Myc helix 1-type peptide fused to an internalization sequence.Cancer Res1998;58:3654-9

[158] Beaulieu ME,Massó-Vallés D.Intrinsic cell-penetrating activity propels Omomyc from proof of concept to viable anti-MYC therapy.Sci Transl Med2019;11:eaar5012 PMCID:PMC6522349

[159] Boise LH.A miRaculous new therapy in myeloma?.Blood2018;132:983-5