Strategies to inhibit Myc and their clinical applicability

Frontiers in Cell and Developmental Biology

Volumn 5, Issue FEB, 2017, Pages

  Whitfield, Jonathan R ^a   Beaulieu, Marie Eve ^b   Soucek, Laura ^a,b,c,d  

^a VALL D HEBRON UNIVERSITY HOSPITAL   (Spain)

^b HOSPITAL UNIVERSITARI VALL D HEBRON   (Spain)

^c INSTITUCIÓ CATALANA DE RECERCA I ESTUDIS AVANÇATS ICREA   (Spain)

^d UNIVERSITAT AUTÒNOMA DE BARCELONA   (Spain)

Author keywords

Clinical application; Inhibitor; Myc; Omomyc; Oncogene; Therapy

Indexed keywords

EID: 85026824000     PISSN: None     EISSN: 2296634X     Source Type: Journal    
DOI: 10.3389/fcell.2017.00010     Document Type: Review

References (154)

1. Abedin, S. M., Boddy, C. S., and Munshi, H. G. (2016). BET inhibitors in the treatment of hematologic malignancies: current insights and future prospects. Onco. Targets Ther. 9, 5943-5953. doi: 10.2147/OTT.S100515
2. Ambrosini, G., Sawle, A. D., Musi, E., and Schwartz, G. K. (2015). BRD4-targeted therapy induces Myc-independent cytotoxicity in Gnaq/11-mutatant uveal melanoma cells. Oncotarget 6, 33397-33409. doi: 10.18632/oncotarget.5179
3. Andrieu, G., Belkina, A. C., and Denis, G. V. (2016). Clinical trials for BET inhibitors run ahead of the science. Drug Discov. Today Technol. 19, 45-50. doi: 10.1016/j.ddtec.2016.06.004
4. Andtbacka, R. H., Kaufman, H. L., Collichio, F., Amatruda, T., Senzer, N., Chesney, J., et al. (2015). Talimogene laherparepvec improves durable response rate in patients with advanced melanoma. J. Clin. Oncol. 33, 2780-2788. doi: 10.1200/JCO.2014.58.3377
5. Annibali, D., Whitfield, J. R., Favuzzi, E., Jauset, T., Serrano, E., Cuartas, I., et al. (2014). Myc inhibition is effective against glioma and reveals a role for Myc in proficient mitosis. Nat. Commun. 5:4632. doi: 10.1038/ncomms5632
6. Arora, V., Knapp, D. C., Smith, B. L., Statdfield, M. L., Stein, D. A., Reddy, M. T., et al. (2000). c-Myc antisense limits rat liver regeneration and indicates role for c-Myc in regulating cytochrome P-450 3A activity. J. Pharmacol. Exp. Ther. 292, 921-928
7. Berg, T., Cohen, S. B., Desharnais, J., Sonderegger, C., Maslyar, D. J., Goldberg, J., et al. (2002). Small-molecule antagonists of Myc/Max dimerization inhibit Myc-induced transformation of chicken embryo fibroblasts. Proc. Natl. Acad. Sci. U.S.A. 99, 3830-3835. doi: 10.1073/pnas.062036999
8. Berthon, C., Raffoux, E., Thomas, X., Vey, N., Gomez-Roca, C., Yee, K., et al. (2016). Bromodomain inhibitor OTX015 in patients with acute leukaemia: a dose-escalation, phase 1 study. Lancet Haematol. 3, e186-e195. doi: 10.1016/S2352-3026(15)00247-1
9. Bid, H. K., Phelps, D. A., Xaio, L., Guttridge, D. C., Lin, J., London, C., et al. (2016). The bromodomain BET inhibitor JQ1 suppresses tumor angiogenesis in models of childhood sarcoma. Mol. Cancer Ther. 15, 1018-1028. doi: 10.1158/1535-7163.MCT-15-0567
10. Bidwell, G. L. III, Perkins, E., Hughes, J., Khan, M., James, J. R., and Raucher, D. (2013). Thermally targeted delivery of a c-Myc inhibitory polypeptide inhibits tumor progression and extends survival in a rat glioma model. PLoS ONE 8:e55104. doi: 10.1371/journal.pone.0055104
11. Bidwell, G. L. III, Perkins, E., and Raucher, D. (2012). A thermally targeted c-Myc inhibitory polypeptide inhibits breast tumor growth. Cancer Lett. 319, 136-143. doi: 10.1016/j.canlet.2011.12.042
12. Brockmann, M., Poon, E., Berry, T., Carstensen, A., Deubzer, H. E., Rycak, L., et al. (2013). Small molecule inhibitors of aurora-a induce proteasomal degradation of N-myc in childhood neuroblastoma. Cancer Cell 24, 75-89. doi: 10.1016/j.ccr.2013.05.005
13. Brooks, T. A., and Hurley, L. H. (2009). The role of supercoiling in transcriptional control of MYC and its importance in molecular therapeutics. Nat. Rev. Cancer 9, 849-861. doi: 10.1038/nrc2733
14. Brooks, T. A., and Hurley, L. H. (2010). Targeting MYC expression through G-quadruplexes. Genes Cancer 1, 641-649. doi: 10.1177/1947601910377493
15. Brown, R. V., Danford, F. L., Gokhale, V., Hurley, L. H., and Brooks, T. A. (2011). Demonstration that drug-targeted down-regulation of MYC in non-hodgkins lymphoma is directly mediated through the promoter G-quadruplex. J. Biol. Chem. 286, 41018-41027. doi: 10.1074/jbc. M111.274720
16. Campaner, S., Doni, M., Hydbring, P., Verrecchia, A., Bianchi, L., Sardella, D., et al. (2010). Cdk2 suppresses cellular senescence induced by the c-myc oncogene. Nat. Cell Biol. 12, 54-59. doi: 10.1038/ncb2004
17. Carroll, P. A., Diolaiti, D., McFerrin, L., Gu, H., Djukovic, D., Du, J., et al. (2015). Deregulated Myc requires MondoA/Mlx for metabolic reprogramming and tumorigenesis. Cancer Cell 27, 271-285. doi: 10.1016/j.ccell.2014.11.024
18. Casey, S. C., Tong, L., Li, Y., Do, R., Walz, S., Fitzgerald, K. N., et al. (2016). MYC regulates the antitumor immune response through CD47 and PD-L1. Science 352, 227-231. doi: 10.1126/science.aac9935
19. Cermelli, S., Jang, I. S., Bernard, B., and Grandori, C. (2014). Synthetic lethal screens as a means to understand and treat MYC-driven cancers. Cold Spring Harb. Perspect. Med. 4:a014209. doi: 10.1101/cshperspect.a014209
20. Chauhan, J., Wang, H., Yap, J. L., Sabato, P. E., Hu, A., Prochownik, E. V., et al. (2014). Discovery of methyl 4'-methyl-5-(7-nitrobenzo[c][1, 2, 5]oxadiazol-4-yl)-[1, 1'-biphenyl]-3-carboxylate, an improved small-molecule inhibitor of c-Myc-max dimerization. ChemMedChem 9, 2274-2285. doi: 10.1002/cmdc.201402189
21. Chen, B. J., Wu, Y. L., Tanaka, Y., and Zhang, W. (2014). Small molecules targeting c-Myc oncogene: promising anti-cancer therapeutics. Int. J. Biol. Sci. 10, 1084-1096. doi: 10.7150/ijbs.10190
22. Chipumuro, E., Marco, E., Christensen, C. L., Kwiatkowski, N., Zhang, T., Hatheway, C. M., et al. (2014). CDK7 inhibition suppresses super-enhancer-linked oncogenic transcription in MYCN-driven cancer. Cell 159, 1126-1139. doi: 10.1016/j.cell.2014.10.024
23. Christensen, C. L., Kwiatkowski, N., Abraham, B. J., Carretero, J., Al-Shahrour, F., Zhang, T., et al. (2014). Targeting transcriptional addictions in small cell lung cancer with a covalent CDK7 inhibitor. Cancer Cell 26, 909-922. doi: 10.1016/j.ccell.2014.10.019
24. Clausen, D. M., Guo, J., Parise, R. A., Beumer, J. H., Egorin, M. J., Lazo, J. S., et al. (2010). In vitro cytotoxicity and in vivo efficacy, pharmacokinetics, and metabolism of 10074-G5, a novel small-molecule inhibitor of c-Myc/Max dimerization. J. Pharmacol. Exp. Ther. 335, 715-727. doi: 10.1124/jpet.110.170555
25. Conacci-Sorrell, M., McFerrin, L., and Eisenman, R. N. (2014). An overview of MYC and its interactome. Cold Spring Harb. Perspect. Med. 4:a014357. doi: 10.1101/cshperspect.a014357
26. Conde, J., Tian, F., Hernández, Y., Bao, C., Cui, D., Janssen, K. P., et al. (2013). In vivo tumor targeting via nanoparticle-mediated therapeutic siRNA coupled to inflammatory response in lung cancer mouse models. Biomaterials 34, 7744-7753. doi: 10.1016/j.biomaterials.2013.06.041
27. Dang, C. V. (2012). MYC on the path to cancer. Cell 149, 22-35. doi: 10.1016/j.cell.2012.03.003
28. Dang, C. V. (2013). MYC, metabolism, cell growth, and tumorigenesis. Cold Spring Harb. Perspect. Med. 3:a014217. doi: 10.1101/cshperspect.a014217
29. Delmore, J. E., Issa, G. C., Lemieux, M. E., Rahl, P. B., Shi, J., Jacobs, H. M., et al. (2011). BET bromodomain inhibition as a therapeutic strategy to target c-Myc. Cell 146, 904-917. doi: 10.1016/j.cell.2011.08.017
30. den Hollander, J., Rimpi, S., Doherty, J. R., Rudelius, M., Buck, A., Hoellein, A., et al. (2010). Aurora kinases A and B are up-regulated by Myc and are essential for maintenance of the malignant state. Blood 116, 1498-1505. doi: 10.1182/blood-2009-11-251074
31. Devi, G. R., Beer, T. M., Corless, C. L., Arora, V., Weller, D. L., and Iversen, P. L. (2005). In vivo bioavailability and pharmacokinetics of a c-MYC antisense phosphorodiamidate morpholino oligomer, AVI-4126, in solid tumors. Clin. Cancer Res. 11, 3930-3938. doi: 10.1158/1078-0432.CCR-04-2091
32. Donato, E., Croci, O., Sabò, A., Muller, H., Morelli, M. J., Pelizzola, M., et al. (2017). Compensatory RNA polymerase 2 loading determines the efficacy and transcriptional selectivity of JQ1 in Myc-driven tumors. Leukemia 31, 479-490. doi: 10.1038/leu.2016.182
33. Drygin, D., Lin, A., Bliesath, J., Ho, C. B., O'Brien, S. E., Proffitt, C., et al. (2011). Targeting RNA polymerase I with an oral small molecule CX-5461 inhibits ribosomal RNA synthesis and solid tumor growth. Cancer Res. 71, 1418-1430. doi: 10.1158/0008-5472.CAN-10-1728
34. Evan, G. (2012). Cancer. Taking a back door to target Myc. Science 335, 293-294. doi: 10.1126/science.1217819
35. Farrell, A. S., Allen-Petersen, B., Daniel, C. J., Wang, X., Wang, Z., Rodriguez, S., et al. (2014). Targeting inhibitors of the tumor suppressor PP2A for the treatment of pancreatic cancer. Mol. Cancer Res. 12, 924-939. doi: 10.1158/1541-7786.MCR-13-0542
36. Felsenstein, K. M., Saunders, L. B., Simmons, J. K., Leon, E., Calabrese, D. R., Zhang, S., et al. (2016). Small molecule microarrays enable the identification of a selective, quadruplex-binding inhibitor of MYC expression. ACS Chem. Biol. 11, 139-148. doi: 10.1021/acschembio.5b00577
37. Ferrao, P. T., Bukczynska, E. P., Johnstone, R. W., and McArthur, G. A. (2012). Efficacy of CHK inhibitors as single agents in MYC-driven lymphoma cells. Oncogene 31, 1661-1672. doi: 10.1038/onc.2011.358
38. Fiorentino, F. P., Tokgüun, E., Solé-Sánchez, S., Giampaolo, S., Tokgun, O., Jauset, T., et al. (2016). Growth suppression by MYC inhibition in small cell lung cancer cells with TP53 and RB1 inactivation. Oncotarget 7, 31014-31028. doi: 10.18632/oncotarget.8826
39. Fletcher, S., and Prochownik, E. V. (2015). Small-molecule inhibitors of the Myc oncoprotein. Biochim. Biophys. Acta 1849, 525-543. doi: 10.1016/j.bbagrm.2014.03.005
40. Follis, A. V., Hammoudeh, D. I., Wang, H., Prochownik, E. V., and Metallo, S. J. (2008). Structural rationale for the coupled binding and unfolding of the c-Myc oncoprotein by small molecules. Chem. Biol. 15, 1149-1155. doi: 10.1016/j.chembiol.2008.09.011
41. Fong, C. Y., Gilan, O., Lam, E. Y., Rubin, A. F., Ftouni, S., Tyler, D., et al. (2015). BET inhibitor resistance emerges from leukaemia stem cells. Nature 525, 538-542. doi: 10.1038/nature14888
42. Galardi, S., Savino, M., Scagnoli, F., Pellegatta, S., Pisati, F., Zambelli, F., et al. (2016). Resetting cancer stem cell regulatory nodes upon MYC inhibition. EMBO Rep. 17, 1872-1889. doi: 10.15252/embr.201541489
43. Garcia, P. L., Miller, A. L., Kreitzburg, K. M., Council, L. N., Gamblin, T. L., Christein, J. D., et al. (2016). The BET bromodomain inhibitor JQ1 suppresses growth of pancreatic ductal adenocarcinoma in patient-derived xenograft models. Oncogene 35, 833-845. doi: 10.1038/onc.2015.126
44. Giorello, L., Clerico, L., Pescarolo, M. P., Vikhanskaya, F., Salmona, M., Colella, G., et al. (1998). Inhibition of cancer cell growth and c-Myc transcriptional activity by a c-Myc helix 1-type peptide fused to an internalization sequence. Cancer Res. 58, 3654-3659
45. Goga, A., Yang, D., Tward, A. D., Morgan, D. O., and Bishop, J. M. (2007). Inhibition of CDK1 as a potential therapy for tumors over-expressing MYC. Nat. Med. 13, 820-827. doi: 10.1038/nm1606
46. Guo, J., Parise, R. A., Joseph, E., Egorin, M. J., Lazo, J. S., Prochownik, E. V., et al. (2009). Efficacy, pharmacokinetics, tisssue distribution, and metabolism of the Myc-Max disruptor, 10058-F4 [Z, E]-5-[4-ethylbenzylidine]-2-thioxothiazolidin-4-one, in mice. Cancer Chemother. Pharmacol. 63, 615-625. doi: 10.1007/s00280-008-0774-y
47. Han, H., Chen, Y., Cheng, L., Prochownik, E. V., and Li, Y. (2016). microRNA-206 impairs c-Myc-driven cancer in a synthetic lethal manner by directly inhibiting MAP3K13. Oncotarget 7, 16409-16419. doi: 10.18632/oncotarget.7653
48. Hart, J. R., Garner, A. L., Yu, J., Ito, Y., Sun, M., Ueno, L., et al. (2014). Inhibitor of MYC identified in a Krohnke pyridine library. Proc. Natl. Acad. Sci. U.S.A. 111, 12556-12561. doi: 10.1073/pnas.1319488111
49. Hartl, M. (2016). The quest for targets executing MYC-dependent cell transformation. Front. Oncol. 6:132. doi: 10.3389/fonc.2016.00132
50. Helm, F., Kammertoens, T., Lehmann, F. M., Wilke, A., Bruns, H., Mautner, J., et al. (2013). Targeting c-MYC with T-cells. PLoS ONE 8:e77375. doi: 10.1371/journal.pone.0077375
51. Hogg, S. J., Newbold, A., Vervoort, S. J., Cluse, L. A., Martin, B. P., Gregory, G. P., et al. (2016). BET inhibition induces apoptosis in aggressive B-cell lymphoma via epigenetic regulation of BCL-2 family members. Mol. Cancer Ther. 15, 2030-2041. doi: 10.1158/1535-7163.MCT-15-0924
52. Horiuchi, D., Camarda, R., Zhou, A. Y., Yau, C., Momcilovic, O., Balakrishnan, S., et al. (2016). PIM1 kinase inhibition as a targeted therapy against triple-negative breast tumors with elevated MYC expression. Nat. Med. 22, 1321-1329. doi: 10.1038/nm.4213
53. Hsieh, A. L., and Dang, C. V. (2016). MYC, metabolic synthetic lethality, and cancer. Recent Results Cancer Res. 207, 73-91. doi: 10.1007/978-3-319-42118-6_4
54. Huang, C. H., Lujambio, A., Zuber, J., Tschaharganeh, D. F., Doran, M. G., Evans, M. J., et al. (2014). CDK9-mediated transcription elongation is required for MYC addiction in hepatocellular carcinoma. Genes Dev. 28, 1800-1814. doi: 10.1101/gad.244368.114
55. Huang, H. L., Weng, H. Y., Wang, L. Q., Yu, C. H., Huang, Q. J., Zhao, P. P., et al. (2012). Triggering Fbw7-mediated proteasomal degradation of c-Myc by oridonin induces cell growth inhibition and apoptosis. Mol. Cancer Ther. 11, 1155-1165. doi: 10.1158/1535-7163.MCT-12-0066
56. Hydbring, P., Bahram, F., Su, Y., Tronnersjo, S., Hogstrand, K., von der Lehr, N., et al. (2010). Phosphorylation by Cdk2 is required for Myc to repress Ras-induced senescence in cotransformation. Proc. Natl. Acad. Sci. U.S.A. 107, 58-63. doi: 10.1073/pnas.0900121106
57. Jain, S., Wang, X., Chang, C. C., Ibarra-Drendall, C., Wang, H., Zhang, Q., et al. (2015). Src inhibition blocks c-Myc translation and glucose metabolism to prevent the development of breast cancer. Cancer Res. 75, 4863-4875. doi: 10.1158/0008-5472.CAN-14-2345
58. Janghorban, M., Farrell, A. S., Allen-Petersen, B. L., Pelz, C., Daniel, C. J., Oddo, J., et al. (2014). Targeting c-MYC by antagonizing PP2A inhibitors in breast cancer. Proc. Natl. Acad. Sci. U.S.A. 111, 9157-9162. doi: 10.1073/pnas.1317630111
59. Jeong, K. C., Kim, K. T., Seo, H. H., Shin, S. P., Ahn, K. O., Ji, M. J., et al. (2014). Intravesical instillation of c-MYC inhibitor KSI-3716 suppresses orthotopic bladder tumor growth. J. Urol. 191, 510-518. doi: 10.1016/j.juro.2013.07.019
60. Jiang, H., Bower, K. E., Beuscher, A. E., Zhou, B., Bobkov, A. A., Olson, A. J., et al. (2009). Stabilizers of the Max homodimer identified in virtual ligand screening inhibit Myc function. Mol. Pharmacol. 76, 491-502. doi: 10.1124/mol.109.054858
61. Jung, K. Y., Wang, H., Teriete, P., Yap, J. L., Chen, L., Lanning, M. E., et al. (2015). Perturbation of the c-Myc-Max protein-protein interaction via synthetic α-helix mimetics. J. Med. Chem. 58, 3002-3024. doi: 10.1021/jm501440q
62. Kessler, J. D., Kahle, K. T., Sun, T., Meerbrey, K. L., Schlabach, M. R., Schmitt, E. M., et al. (2012). A SUMOylation-dependent transcriptional subprogram is required for Myc-driven tumorigenesis. Science 335, 348-353. doi: 10.1126/science.1212728
63. Kipshidze, N., Iversen, P., Overlie, P., Dunlap, T., Titus, B., Lee, D., et al. (2007). First human experience with local delivery of novel antisense AVI-4126 with Infiltrator catheter in de novo native and restenotic coronary arteries: 6-month clinical and angiographic follow-up from AVAIL study. Cardiovasc. Revasc. Med. 8, 230-235. doi: 10.1016/j.carrev.2007.04.002
64. Kipshidze, N. N., Iversen, P., Kim, H. S., Yiazdi, H., Dangas, G., Seaborn, R., et al. (2004). Advanced c-myc antisense (AVI-4126)-eluting phosphorylcholine-coated stent implantation is associated with complete vascular healing and reduced neointimal formation in the porcine coronary restenosis model. Catheter. Cardiovasc. Interv. 61, 518-527. doi: 10.1002/ccd.20007
65. Kipshidze, N. N., Porter, T. R., Dangas, G., Yazdi, H., Tio, F., Xie, F., et al. (2003). Systemic targeted delivery of antisense with perflourobutane gas microbubble carrier reduced neointimal formation in the porcine coronary restenosis model. Cardiovasc. Radiat. Med. 4, 152-159. doi: 10.1016/S1522-1865(03)00184-7
66. Koh, C. M., Sabo, A., and Guccione, E. (2016). Targeting MYC in cancer therapy: RNA processing offers new opportunities. Bioessays 38, 266-275. doi: 10.1002/bies.201500134
67. Kumar, A., Ito, A., Hirohama, M., Yoshida, M., and Zhang, K. Y. (2016). Identification of new SUMO activating enzyme 1 inhibitors using virtual screening and scaffold hopping. Bioorg. Med. Chem. Lett. 26, 1218-1223. doi: 10.1016/j.bmcl.2016.01.030
68. Kwiatkowski, N., Zhang, T., Rahl, P. B., Abraham, B. J., Reddy, J., Ficarro, S. B., et al. (2014). Targeting transcription regulation in cancer with a covalent CDK7 inhibitor. Nature 511, 616-620. doi: 10.1038/nature13393
69. Lapenna, S., and Giordano, A. (2009). Cell cycle kinases as therapeutic targets for cancer. Nat. Rev. Drug Discov. 8, 547-566. doi: 10.1038/nrd2907
70. Lazo, J. S., and Sharlow, E. R. (2016). Drugging undruggable molecular cancer targets. Annu. Rev. Pharmacol. Toxicol. 56, 23-40. doi: 10.1146/annurev-pharmtox-010715-103440
71. Li, L., Sun, W., Zhang, Z., and Huang, Y. (2016). Time-staggered delivery of docetaxel and H1-S6A, F8A peptide for sequential dual-strike chemotherapy through tumor priming and nuclear targeting. J. Control. Release 232, 62-74. doi: 10.1016/j.jconrel.2016.04.021
72. Li, X., Zhang, X. A., Li, X., Xie, W., and Huang, S. (2015). MYC-mediated synthetic lethality for treating tumors. Curr. Cancer Drug Targets 15, 99-115. doi: 10.2174/1568009615666150121162921
73. Li, Y., Zhang, B., Zhang, H., Zhu, X., Feng, D., Zhang, D., et al. (2013). Oncolytic adenovirus armed with shRNA targeting MYCN gene inhibits neuroblastoma cell proliferation and in vivo xenograft tumor growth. J. Cancer Res. Clin. Oncol. 139, 933-941. doi: 10.1007/s00432-013-1406-4
74. Liu, L., Ulbrich, J., Muller, J., Wustefeld, T., Aeberhard, L., Kress, T. R., et al. (2012). Deregulated MYC expression induces dependence upon AMPK-related kinase 5. Nature 483, 608-612. doi: 10.1038/nature10927
75. Loven, J., Hoke, H. A., Lin, C. Y., Lau, A., Orlando, D. A., Vakoc, C. R., et al. (2013). Selective inhibition of tumor oncogenes by disruption of super-enhancers. Cell 153, 320-334. doi: 10.1016/j.cell.2013.03.036
76. Macarulla, T., Cervantes, A., Elez, E., Rodriguez-Braun, E., Baselga, J., Rosello, S., et al. (2010). Phase I study of the selective Aurora A kinase inhibitor MLN8054 in patients with advanced solid tumors: safety, pharmacokinetics, and pharmacodynamics. Mol. Cancer Ther. 9, 2844-2852. doi: 10.1158/1535-7163.MCT-10-0299
77. Massó-Vallés, D., Jauset, T., and Soucek, L. (2016). Ibrutinib repurposing: from B-cell malignancies to solid tumors. Oncoscience 3, 147-148. doi: 10.18632/oncoscience.310
78. McKeown, M. R., and Bradner, J. E. (2014). Therapeutic strategies to inhibit MYC. Cold Spring Harb. Perspect. Med. 4:a014266. doi: 10.1101/cshperspect.a014266
79. Mertz, J. A., Conery, A. R., Bryant, B. M., Sandy, P., Balasubramanian, S., Mele, D. A., et al. (2011). Targeting MYC dependence in cancer by inhibiting BET bromodomains. Proc. Natl. Acad. Sci. U.S.A. 108, 16669-16674. doi: 10.1073/pnas.1108190108
80. Meyer, N., and Penn, L. Z. (2008). Reflecting on 25 years with MYC. Nat. Rev. Cancer 8, 976-990. doi: 10.1038/nrc2231
81. Mo, H., and Henriksson, M. (2006). Identification of small molecules that induce apoptosis in a Myc-dependent manner and inhibit Myc-driven transformation. Proc. Natl. Acad. Sci. U.S.A. 103, 6344-6349. doi: 10.1073/pnas.0601418103
82. Mo, H., Vita, M., Crespin, M., and Henriksson, M. A. (2006). Myc overexpression enhances apoptosis induced by small molecules. Cell Cycle 5, 2191-2194. doi: 10.4161/cc.5.19.3320
83. Montagne, M., Beaudoin, N., Fortin, D., Lavoie, C. L., Klinck, R., and Lavigne, P. (2012). The max b-HLH-LZ can transduce into cells and inhibit c-Myc transcriptional activities. PLoS ONE 7:e32172. doi: 10.1371/journal.pone.0032172
84. Moreno, P. M., and Pego, A. P. (2014). Therapeutic antisense oligonucleotides against cancer: hurdling to the clinic. Front. Chem. 2:87. doi: 10.3389/fchem.2014.00087
85. Murga, M., Campaner, S., Lopez-Contreras, A. J., Toledo, L. I., Soria, R., Montana, M. F., et al. (2011). Exploiting oncogene-induced replicative stress for the selective killing of Myc-driven tumors. Nat. Struct. Mol. Biol. 18, 1331-1335. doi: 10.1038/nsmb.2189
86. Nair, S. K., and Burley, S. K. (2003). X-ray structures of Myc-Max and Mad-Max recognizing DNA. Molecular bases of regulation by proto-oncogenic transcription factors. Cell 112, 193-205. doi: 10.1016/S0092-8674(02)01284-9
87. Nanbru, C., Lafon, I., Audigier, S., Gensac, M. C., Vagner, S., Huez, G., et al. (1997). Alternative translation of the proto-oncogene c-myc by an internal ribosome entry site. J. Biol. Chem. 272, 32061-32066
88. Neidle, S. (2016). Quadruplex nucleic acids as novel therapeutic targets. J. Med. Chem. 59, 5987-6011. doi: 10.1021/acs.jmedchem.5b01835
89. Nilson, K. A., Guo, J., Turek, M. E., Brogie, J. E., Delaney, E., Luse, D. S., et al. (2015). THZ1 Reveals Roles for Cdk7 in Co-transcriptional Capping and Pausing. Mol. Cell 59, 576-587. doi: 10.1016/j.molcel.2015.06.032
90. Ortega, S., Prieto, I., Odajima, J., Martin, A., Dubus, P., Sotillo, R., et al. (2003). Cyclin-dependent kinase 2 is essential for meiosis but not for mitotic cell division in mice. Nat. Genet. 35, 25-31. doi: 10.1038/ng1232
91. Otto, T., Horn, S., Brockmann, M., Eilers, U., Schuttrumpf, L., Popov, N., et al. (2009). Stabilization of N-Myc is a critical function of Aurora A in human neuroblastoma. Cancer Cell 15, 67-78. doi: 10.1016/j.ccr.2008.12.005
92. Ou, T. M., Lu, Y. J., Zhang, C., Huang, Z. S., Wang, X. D., Tan, J. H., et al. (2007). Stabilization of G-quadruplex DNA and down-regulation of oncogene c-myc by quindoline derivatives. J. Med. Chem. 50, 1465-1474. doi: 10.1021/jm0610088
93. Patel, M. R., and Kratzke, R. A. (2013). Oncolytic virus therapy for cancer: the first wave of translational clinical trials. Transl. Res. 161, 355-364. doi: 10.1016/j.trsl.2012.12.010
94. Peter, S., Bultinck, J., Myant, K., Jaenicke, L. A., Walz, S., Muller, J., et al. (2014). Tumor cell-specific inhibition of MYC function using small molecule inhibitors of the HUWE1 ubiquitin ligase. EMBO Mol. Med. 6, 1525-1541. doi: 10.15252/emmm.201403927
95. Philipp, S., Sack, S., Kordish, I., Brachmann, J., Hardt, S., Horn, J., et al. (2012). The appraisal-trial: evaluating RESTEN-MPTM in patients with bare metal stent de novo native coronary artery lesions. J. Clin. Exp. Cardiolog. 3:218. doi: 10.4172/2155-9880.1000218
96. Pivetta, C., Lucatello, L., Krapcho, A. P., Gatto, B., Palumbo, M., and Sissi, C. (2008). Perylene side chains modulate G-quadruplex conformation in biologically relevant DNA sequences. Bioorg. Med. Chem. 16, 9331-9339. doi: 10.1016/j.bmc.2008.08.068
97. Polivka, J. Jr., and Janku, F. (2014). Molecular targets for cancer therapy in the PI3K/AKT/mTOR pathway. Pharmacol. Ther. 142, 164-175. doi: 10.1016/j.pharmthera.2013.12.004
98. Poortinga, G., Quinn, L. M., and Hannan, R. D. (2015). Targeting RNA polymerase I to treat MYC-driven cancer. Oncogene 34, 403-412. doi: 10.1038/onc.2014.13
99. Posternak, V., and Cole, M. D. (2016). Strategically targeting MYC in cancer. F1000Res. 5:F1000 Faculty Rev-408. doi: 10.12688/f1000research.7879.1
100. Prochownik, E. V., Kukowska, J., and Rodgers, C. (1988). c-myc antisense transcripts accelerate differentiation and inhibit G1 progression in murine erythroleukemia cells. Mol. Cell. Biol. 8, 3683-3695. doi: 10.1128/MCB.8.9.3683
101. Prochownik, E. V., and Vogt, P. K. (2010). Therapeutic targeting of Myc. Genes Cancer 1, 650-659. doi: 10.1177/1947601910377494
102. Rathert, P., Roth, M., Neumann, T., Muerdter, F., Roe, J. S., Muhar, M., et al. (2015). Transcriptional plasticity promotes primary and acquired resistance to BET inhibition. Nature 525, 543-547. doi: 10.1038/nature14898
103. Richart, L., Carrillo-de Santa Pau, E., Rio-Machin, A., de Andres, M. P., Cigudosa, J. C., Lobo, V. J., et al. (2016a). BPTF is required for c-MYC transcriptional activity and in vivo tumorigenesis. Nat. Commun. 7:10153. doi: 10.1038/ncomms10153
104. Richart, L., Real, F. X., and Sanchez-Arevalo Lobo, V. J. (2016b). c-MYC partners with BPTF in human cancer. Mol. Cell Oncol. 3:e1152346. doi: 10.1080/23723556.2016.1152346
105. Roohi, A., and Hojjat-Farsangi, M. (2016). Recent advances in targeting mTOR signaling pathway using small molecule inhibitors. J. Drug Target. doi: 10.1080/1061186X.2016.1236112. [Epub ahead of print]
106. Savino, M., Annibali, D., Carucci, N., Favuzzi, E., Cole, M. D., Evan, G. I., et al. (2011). The action mechanism of the Myc inhibitor termed Omomyc may give clues on how to target Myc for cancer therapy. PLoS ONE 6:e22284. doi: 10.1371/journal.pone.0022284
107. Sears, R. C. (2004). The life cycle of C-myc: from synthesis to degradation. Cell Cycle 3, 1133-1137. doi: 10.4161/cc.3.9.1145
108. Seo, H. K., Ahn, K. O., Jung, N. R., Shin, J. S., Park, W. S., Lee, K. H., et al. (2014). Antitumor activity of the c-Myc inhibitor KSI-3716 in gemcitabine-resistant bladder cancer. Oncotarget 5, 326-337. doi: 10.18632/oncotarget.1545
109. Shaat, H., Mostafa, A., Moustafa, M., Gamal-Eldeen, A., Emam, A., El-Hussieny, E., et al. (2016). Modified gold nanoparticles for intracellular delivery of anti-liver cancer siRNA. Int. J. Pharm. 504, 125-133. doi: 10.1016/j.ijpharm.2016.03.051
110. Shalaby, T., and Grotzer, M. A. (2016). MYC as therapeutic target for embryonal tumors: potential and challenges. Curr. Cancer Drug Targets 16, 2-21. doi: 10.2174/1568009615666150916092745
111. Shapiro, G. I., Dowlati, A., LoRusso, P. M., Eder, J. P., Anderson, A., Do, K. T., et al. (2015). Abstract A49: Clinically efficacy of the BET bromodomain inhibitor TEN-010 in an open-label substudy with patients with documented NUT-midline carcinoma (NMC). Mol. Cancer Ther. 14(12Suppl.2):A49. doi: 10.1158/1535-7163.TARG-15-A49
112. Shi, X., Mihaylova, V. T., Kuruvilla, L., Chen, F., Viviano, S., Baldassarre, M., et al. (2016). Loss of TRIM33 causes resistance to BET bromodomain inhibitors through MYC-and TGF-beta-dependent mechanisms. Proc. Natl. Acad. Sci. U.S.A. 113, E4558-E4566. doi: 10.1073/pnas.1608319113
113. Shim, H., Chun, Y. S., Lewis, B. C., and Dang, C. V. (1998). A unique glucose-dependent apoptotic pathway induced by c-Myc. Proc. Natl. Acad. Sci. U.S.A. 95, 1511-1516
114. Shimamura, T., Chen, Z., Soucheray, M., Carretero, J., Kikuchi, E., Tchaicha, J. H., et al. (2013). Efficacy of BET bromodomain inhibition in Kras-mutant non-small cell lung cancer. Clin. Cancer Res. 19, 6183-6192. doi: 10.1158/1078-0432.CCR-12-3904
115. Simonsson, T., Pecinka, P., and Kubista, M. (1998). DNA tetraplex formation in the control region of c-myc. Nucleic Acids Res. 26, 1167-1172
116. Sklar, M. D., Thompson, E., Welsh, M. J., Liebert, M., Harney, J., Grossman, H. B., et al. (1991). Depletion of c-myc with specific antisense sequences reverses the transformed phenotype in ras oncogene-transformed NIH 3T3 cells. Mol. Cell. Biol. 11, 3699-3710. doi: 10.1128/MCB.11.7.3699
117. Smith, M. R. (2015). Ibrutinib in B lymphoid malignancies. Expert Opin. Pharmacother. 16, 1879-1887. doi: 10.1517/14656566.2015.1067302
118. Sodir, N. M., Swigart, L. B., Karnezis, A. N., Hanahan, D., Evan, G. I., and Soucek, L. (2011). Endogenous Myc maintains the tumor microenvironment. Genes Dev. 25, 907-916. doi: 10.1101/gad.2038411
119. Soodgupta, D., Pan, D., Cui, G., Senpan, A., Yang, X., Lu, L., et al. (2015). Small molecule MYC inhibitor conjugated to integrin-targeted nanoparticles extends survival in a mouse model of disseminated multiple myeloma. Mol. Cancer Ther. 14, 1286-1294. doi: 10.1158/1535-7163.MCT-14-0774-T
120. Soucek, L., Buggy, J. J., Kortlever, R., Adimoolam, S., Monclus, H. A., Allende, M. T., et al. (2011). Modeling pharmacological inhibition of mast cell degranulation as a therapy for insulinoma. Neoplasia 13, 1093-1100. doi: 10.1593/neo.11980
121. Soucek, L., and Evan, G. (2002). Myc-Is this the oncogene from Hell? Cancer Cell 1, 406-408. doi: 10.1016/S1535-6108(02)00077-6
122. Soucek, L., Helmer-Citterich, M., Sacco, A., Jucker, R., Cesareni, G., and Nasi, S. (1998). Design and properties of a Myc derivative that efficiently homodimerizes. Oncogene 17, 2463-2472. doi: 10.1038/sj.onc.1202199
123. Soucek, L., Jucker, R., Panacchia, L., Ricordy, R., Tato, F., and Nasi, S. (2002). Omomyc, a potential Myc dominant negative, enhances Myc-induced apoptosis. Cancer Res. 62, 3507-3510
124. Soucek, L., Lawlor, E. R., Soto, D., Shchors, K., Swigart, L. B., and Evan, G. I. (2007). Mast cells are required for angiogenesis and macroscopic expansion of Myc-induced pancreatic islet tumors. Nat. Med. 13, 1211-1218. doi: 10.1038/nm1649
125. Soucek, L., Nasi, S., and Evan, G. I. (2004). Omomyc expression in skin prevents Myc-induced papillomatosis. Cell Death Differ. 11, 1038-1045. doi: 10.1038/sj.cdd.4401443
126. Soucek, L., Whitfield, J., Martins, C. P., Finch, A. J., Murphy, D. J., Sodir, N. M., et al. (2008). Modelling Myc inhibition as a cancer therapy. Nature 455, 679-683. doi: 10.1038/nature07260
127. Soucek, L., Whitfield, J. R., Sodir, N. M., Massó-Vallés, D., Serrano, E., Karnezis, A. N., et al. (2013). Inhibition of Myc family proteins eradicates KRas-driven lung cancer in mice. Genes Dev. 27, 504-513. doi: 10.1101/gad.205542.112
128. Stellas, D., Szabolcs, M., Koul, S., Li, Z., Polyzos, A., Anagnostopoulos, C., et al. (2014). Therapeutic effects of an anti-Myc drug on mouse pancreatic cancer. J. Natl. Cancer Inst. 106:dju320. doi: 10.1093/jnci/dju320
129. Sun, K., Atoyan, R., Borek, M. A., DellaRocca, S., Samson, M. E., Ma, A. W., et al. (2016). Dual HDAC and PI3K inhibitor CUDC-907 downregulates MYC and suppresses growth of MYC-dependent cancers. Mol. Cancer Ther. 16, 285-299. doi: 10.1158/1535-7163.MCT-16-0390
130. Sun, X. X., Sears, R. C., and Dai, M. S. (2015). Deubiquitinating c-Myc: USP36 steps up in the nucleolus. Cell Cycle 14, 3786-3793. doi: 10.1080/15384101.2015.1093713
131. Thomas, L. R., Foshage, A. M., Weissmiller, A. M., and Tansey, W. P. (2015). The MYC-WDR5 nexus and cancer. Cancer Res. 75, 4012-4015. doi: 10.1158/0008-5472.CAN-15-1216
132. Tolcher, A. W., Papadopoulos, K. P., Patnaik, A., Rasco, D. W., Martinez, D., Wood, D. L., et al. (2015). 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. J. Clin. Oncol. 33(Suppl; abstr 11006)
133. Toyoshima, M., Howie, H. L., Imakura, M., Walsh, R. M., Annis, J. E., Chang, A. N., et al. (2012). Functional genomics identifies therapeutic targets for MYC-driven cancer. Proc. Natl. Acad. Sci. U.S.A. 109, 9545-9550. doi: 10.1073/pnas.1121119109
134. Wang, H., Chauhan, J., Hu, A., Pendleton, K., Yap, J. L., Sabato, P. E., et al. (2013). Disruption of Myc-Max heterodimerization with improved cell-penetrating analogs of the small molecule 10074-G5. Oncotarget 4, 936-947. doi: 10.18632/oncotarget.1108
135. Wang, H., Hammoudeh, D. I., Follis, A. V., Reese, B. E., Lazo, J. S., Metallo, S. J., et al. (2007). Improved low molecular weight Myc-Max inhibitors. Mol. Cancer Ther. 6, 2399-2408. doi: 10.1158/1535-7163.MCT-07-0005
136. Wang, H., Mannava, S., Grachtchouk, V., Zhuang, D., Soengas, M. S., Gudkov, A. V., et al. (2008). c-Myc depletion inhibits proliferation of human tumor cells at various stages of the cell cycle. Oncogene 27, 1905-1915. doi: 10.1038/sj.onc.1210823
137. Wang, H., Ramakrishnan, A., Fletcher, S., and Prochownik, E. V. (2015a). A quantitative, surface plasmon resonance-based approach to evaluating DNA binding by the c-Myc oncoprotein and its disruption by small molecule inhibitors. J. Biol. Methods 2:e18. doi: 10.14440/jbm.2015.54
138. Wang, H., Teriete, P., Hu, A., Raveendra-Panickar, D., Pendelton, K., Lazo, J. S., et al. (2015b). Direct inhibition of c-Myc-Max heterodimers by celastrol and celastrol-inspired triterpenoids. Oncotarget 6, 32380-32395. doi: 10.18632/oncotarget.6116
139. Wang, Y., Engels, I. H., Knee, D. A., Nasoff, M., Deveraux, Q. L., and Quon, K. C. (2004). Synthetic lethal targeting of MYC by activation of the DR5 death receptor pathway. Cancer Cell 5, 501-512. doi: 10.1016/S1535-6108(04)00113-8
140. Wang, Y., Zhang, T., Kwiatkowski, N., Abraham, B. J., Lee, T. I., Xie, S., et al. (2015c). CDK7-dependent transcriptional addiction in triple-negative breast cancer. Cell 163, 174-186. doi: 10.1016/j.cell.2015.08.063
141. Webb, M. S., Tortora, N., Cremese, M., Kozlowska, H., Blaquiere, M., Devine, D. V., et al. (2004). Toxicity and toxicokinetics of a phosphorothioate oligonucleotide against the c-myc oncogene in cynomolgus monkeys. Antisense Nucleic Acid Drug Dev. 11, 155-163. doi: 10.1089/108729001300338681
142. Westermarck, J., and Hahn, W. C. (2008). Multiple pathways regulated by the tumor suppressor PP2A in transformation. Trends Mol. Med. 14, 152-160. doi: 10.1016/j.molmed.2008.02.001
143. Whitfield, J. R., and Soucek, L. (2012). Tumor microenvironment: becoming sick of Myc. Cell. Mol. Life Sci. 69, 931-934. doi: 10.1007/s00018-011-0860-x
144. Wiegering, A., Uthe, F. W., Jamieson, T., Ruoss, Y., Huttenrauch, M., Kuspert, M., et al. (2015). Targeting translation initiation bypasses signaling crosstalk mechanisms that maintain high MYC levels in colorectal cancer. Cancer Discov. 5, 768-781. doi: 10.1158/2159-8290.CD-14-1040
145. Wu, P., Ma, D. L., Leung, C. H., Yan, S. C., Zhu, N., Abagyan, R., et al. (2009). Stabilization of G-quadruplex DNA with platinum(II) Schiffbase complexes: luminescent probe and down-regulation of c-myc oncogene expression. Chemistry 15, 13008-13021. doi: 10.1002/chem.200901943
146. Xu, Y., Shi, J., Yamamoto, N., Moss, J. A., Vogt, P. K., and Janda, K. D. (2006). A credit-card library approach for disrupting protein-protein interactions. Bioorg. Med. Chem. 14, 2660-2673. doi: 10.1016/j.bmc.2005.11.052
147. Yang, D., Liu, H., Goga, A., Kim, S., Yuneva, M., and Bishop, J. M. (2010). Therapeutic potential of a synthetic lethal interaction between the MYC proto-oncogene and inhibition of aurora-B kinase. Proc. Natl. Acad. Sci. U.S.A. 107, 13836-13841. doi: 10.1073/pnas.1008366107
148. Yao, W., Yue, P., Khuri, F. R., and Sun, S. Y. (2015). The BET bromodomain inhibitor, JQ1, facilitates c-FLIP degradation and enhances TRAIL-induced apoptosis independent of BRD4 and c-Myc inhibition. Oncotarget 6, 34669-34679. doi: 10.18632/oncotarget.5785
149. Yap, J. L., Wang, H., Hu, A., Chauhan, J., Jung, K. Y., Gharavi, R. B., et al. (2013). Pharmacophore identification of c-Myc inhibitor 10074-G5. Bioorg. Med. Chem. Lett. 23, 370-374. doi: 10.1016/j.bmcl.2012.10.013
150. Yin, X., Giap, C., Lazo, J. S., and Prochownik, E. V. (2003). Low molecular weight inhibitors of Myc-Max interaction and function. Oncogene 22, 6151-6159. doi: 10.1038/sj.onc.1206641
151. Yu, C., Niu, X., Jin, F., Liu, Z., Jin, C., and Lai, L. (2016). Structure-based inhibitor design for the intrinsically disordered protein c-myc. Sci. Rep. 6:22298. doi: 10.1038/srep22298
152. Yuneva, M., Zamboni, N., Oefner, P., Sachidanandam, R., and Lazebnik, Y. (2007). Deficiency in glutamine but not glucose induces MYC-dependent apoptosis in human cells. J. Cell Biol. 178, 93-105. doi: 10.1083/jcb.200703099
153. Zhang, Y., Peng, L., Mumper, R. J., and Huang, L. (2013). Combinational delivery of c-myc siRNA and nucleoside analogs in a single, synthetic nanocarrier for targeted cancer therapy. Biomaterials 34, 8459-8468. doi: 10.1016/j.biomaterials.2013.07.050
154. Zhu, Q., Feng, C., Liao, W., Zhang, Y., and Tang, S. (2013). Target delivery of MYCN siRNA by folate-nanoliposomes delivery system in a metastatic neuroblastoma model. Cancer Cell Int. 13:65. doi: 10.1186/1475-2867-13-65