Chromatin Addiction in NUT Carcinoma: Targeted Epigenetic Pharmacology Beyond BET Inhibition
Abstract
NUT Carcinoma (NC) is most aggressive cancer caused due to the NUTM1/BRD4 alteration which generates BRD4-NUT oncoprotein leads to the inadequate activation of chromatin then its blocks the differentiation1,3. This fusion mediated cancer is symbol of broader pathology called as Chromatin addiction, in this dangerous cell become reliant on non-standard epigenomic landscapes for the ability to survive and spread. Traditional medicine policies have targeted the bromodomain & extra terminal domain (BET) proteins for identifies acetyl-lysine moieties of histones for oncogenic transcription. BET inhibitors (BETi’s) such as JQ1 and its clinical analogues changes the position of BRD4-NUT from the chromatin, it responsible to suppress expression of oncogenes & promote differentiation with only modest or temporary clinical responses, which highlighting the needs for additional therapeutic strategies1-4. Now days, it has become clear that the epigenetic terrain of NC also includes reciprocal dependencies other than abnormal acetylation.
Inhibitory chromatin compounds that are the Polycom repressive complex 2 (PRC2) and its enzyme EZH2 have been identified to play a crucial role in tumorigenesis via silencing of tumour suppressor genes6. That means EZH2 is inhibited by haemostat then we clearly see a restoration of the silenced tumour suppressors and produce a synergistic effect with BET inhibition which in turn to reduces proliferation, it promotes differentiation & stop the tumour growth in preclinical NC models7. The other epigenetic modifiers like p300/CBP histone acetyltransferases that's targets on tumoral activity and work by BETi’s8. Then all the results are put forth a model of targeted epigenetic therapy beyond the use of BET inhibitors for NC which promotes the use of combination and multi targeted strategies to get over and minimize epigenetic dependence and resistance.
Keywords: Oncogene addiction, NUT Carcinoma, Chromatin addiction, BET inhibition
Keywords:
Oncogene addiction, NUT Carcinoma, Chromatin addictionDOI
https://doi.org/10.22270/jddt.v16i3.7640References
1. NUT carcinoma (NC; formerly NUT midline carcinoma) is defined by NUTM1 chromosomal rearrangements and BRD-NUT fusion oncogenes, resulting in aggressive clinical behaviour. Wikipedia. 2025. https://en.wikipedia.org/wiki/NUT_carcinoma
2. The BRD4-NUT oncoprotein forms hyperacetylated “mega domains” that drive oncogenic transcription and block differentiation. Wang et al., Trans Cancer Res. 2025.https://pmc.ncbi.nlm.nih.gov/articles/PMC9870903/
3. BET inhibitors compete with acetyl-lysine interactions to displace BRD4-NUT from chromatin, demonstrating preclinical efficacy but limited clinical durability. NUTM1-Rearranged Neoplasms, MDPI Cancer 2025. https://www.mdpi.com/journal/cancers/special_issues/NUTM1_Neoplasia
4. Jones PA, Issa JP, Baylin S. Targeting the cancer epigenome for therapy. Nat Rev Genet. 2016;17(10):630-641. https://www.nature.com/articles/nrg.2016.93
5. EZH2, a PRC2 histone methyltransferase, is a dependency in NC; its inhibition with haemostats reverses repressive chromatin marks and synergizes with BET inhibitors to suppress NC growth. Huang et al., Cancer Res. Alekseyenko 2023. https://pubmed.ncbi.nlm.nih.gov/37747726/
6. Commentary on epigenetic cooperativity in NC highlights the therapeutic synergy of combining EZH2 inhibition with BET inhibition. Epigenetic Cooperativity, Cancer Res 2023. https://pubmed.ncbi.nlm.nih.gov/38037453/
7. p300/CBP histone acetyltransferase inhibition disrupts BRD4-NUT function and synergizes with BET inhibitors, identifying alternative epigenetic targets. Therapeutic targeting of p300/CBP HAT, Oncogene. 2020. https://pubmed.ncbi.nlm.nih.gov/32366905/
8. French CA. NUT carcinoma: clinicopathologic features, diagnosis, and molecular genetics. Patho Int. 2018. https://pubmed.ncbi.nlm.nih.gov/32366905/
9. French CA, et al. BRD4-NUT fusion oncogene: a unique mechanism of transcriptional dysregulation in carcinoma. Cancer Res. 2003. https://pubmed.ncbi.nlm.nih.gov/12543779/
10. Bauer DE, et al. Clinicopathologic features and long-term outcomes of NUT carcinoma. J Clin Oncol. 2012. https://pubmed.ncbi.nlm.nih.gov/22851582/
11. Chau NG, et al. Aggressive clinical behaviour and poor outcomes in NUT carcinoma. Cancer. 2016. https://pubmed.ncbi.nlm.nih.gov/27509377/
12. Stelow EB. A review of NUT carcinoma. Head Neck Pathol. 2011. https://pubmed.ncbi.nlm.nih.gov/21246463
13. Haack H, et al. Diagnosis of NUT midline carcinoma using NUT-specific monoclonal antibodies. Am J Surg Pathol. 2009. https://pubmed.ncbi.nlm.nih.gov/19510026/
14. Reynoird N, et al. Oncogenesis by sequestration of histone acetyltransferases in NUT carcinoma. EMBO J. 2010. https://link.springer.com/article/10.1038/emboj.2010.176
15. Bradner JE, et al. Transcriptional addiction in cancer and therapeutic targeting of chromatin regulators. Cell. 2017. https://pubmed.ncbi.nlm.nih.gov/28125750/
16. Filippakopoulos P, et al. Selective inhibition of BET bromodomains. Nature. 2010.https://pubmed.ncbi.nlm.nih.gov/20871596/
17. Tanaka M, et al. Epigenetic vulnerabilities and combination strategies in NUT carcinoma. Cancer Res. 2023. https://pubmed.ncbi.nlm.nih.gov/37747726/
18. AA, et al. The oncogenic BRD4-NUT chromatin regulator drives abnormal transcriptional activation. Genes Dev. 2015. https://pubmed.ncbi.nlm.nih.gov/26220994/
19. Grayson AR, et al. BRD3-NUT oncogenic fusion drives NUT carcinoma through chromatin dysregulation. Mol Cell Biol. 2014. https://pubmed.ncbi.nlm.nih.gov/25378525/
20. French CA, et al. NSD3-NUT fusion oncogene in NUT carcinoma. Genes Chromosomes Cancer. 2014. https://pubmed.ncbi.nlm.nih.gov/25131729/
21. Weinstein IB. Addiction to oncogenes-the Achilles heel of cancer. Science. 2002;297:63-64. https://pubmed.ncbi.nlm.nih.gov/12098689/
22. Dawson MA, Kouzarides T. Cancer epigenetics: from mechanism to therapy. Cell. 2012;150:12-27. https://pubmed.ncbi.nlm.nih.gov/22770212/
23. Kummar S, Williams PM, Lih CJ, et al. Application of molecular profiling in clinical trials for rare cancers. J Clin Oncol. 2015;33(24):2755-2762. https://pmc.ncbi.nlm.nih.gov/articles/PMC4334817
24. Mohammad HP, Helin K. Oncohistones: drivers of pediatric cancers. Genes Dev. 2017;31:2313-2324. https://pmc.ncbi.nlm.nih.gov/articles/PMC5795778/
25. Beroukhim R, et al. The landscape of somatic copy-number alteration across human cancers. Nature. 2010;463:899-905. https://pubmed.ncbi.nlm.nih.gov/
26. Hnisz D, et al. Super-enhancers in the control of cell identity and disease. Cell. 2013;155:934-947. https://pubmed.ncbi.nlm.nih.gov/
27. Filippakopoulos P, Knapp S. Targeting bromodomains: epigenetic readers of lysine acetylation. Nat Rev Drug Discov. 2014;13:337-356. https://pubmed.ncbi.nlm.nih.gov/
28. McKeown MR, Bradner JE. Therapeutic strategies to inhibit transcriptional drivers in cancer. Cell. 2014;158:26-41 . https://pubmed.ncbi.nlm.nih.gov/
29. Northcott PA, et al. Enhancer hijacking activates GFI1 family oncogenes in medulloblastoma. Nature. 2014;511:428-434. https://pubmed.ncbi.nlm.nih.gov/
30. Flavahan WA, et al. Insulator dysfunction and oncogene activation in IDH mutant gliomas. Nature. 2016;529:110-114. https://pubmed.ncbi.nlm.nih.gov/
31. Helming KC, Wang X, Roberts CWM. Vulnerabilities of mutant SWI/SNF complexes in cancer. Cancer Cell. 2014;26:309-317. https://doi.org/10.1016/j.ccr.2014.07.018
32. Bennett RL, Licht JD. Targeting epigenetics in cancer. Annu Rev Pharmacol Toxicol. 2018;58:187-207. https://doi.org/10.1146/annurev-pharmtox-010617-052933
33. Kuo AJ, et al. NSD2 links dimethylation of H3K36 to oncogenic programming. Mol Cell. 2011;44(4):609-620. https://doi.org/10.1016/j.molcel.2011.08.042
34. Lucio-Eterovic AK, et al. Role of the NSD family in chromatin regulation. Epigenetics. 2011;6(5):518-524. https://doi.org/10.4161/epi.6.5.14930
35. McCabe MT, et al. EZH2 inhibition as a therapeutic strategy. Epigenomics. 2012;4(2):113-128. https://doi.org/10.2217/epi.12.8
36. Nagarajan S, et al. Chromatin topology reorganization by BRD4-NUT fusion proteins. Nat Struct Mol Biol. 2017;24:800-810. https://doi.org/10.1038/nsmb.3458
37. Italiano A, et al. Tazemetostat in advanced epithelioid sarcoma. Lancet Oncol. 2020;21(11):1423-1432. https://doi.org/10.1016/S1470-2045(20)30471-2
38. Hidalgo M, Amant F, Biankin AV, et al. Patient-derived xenograft models: an emerging platform for translational cancer research. Cancer Discov. 2014;4(9):998-1013. https://doi.org/10.1158/2159-8290.CD-14-0001
39. Kim KH, Roberts CW. Targeting EZH2 in cancer. Nat Med. 2016;22(2):128-134. https://doi.org/10.1038/nm.4036
40. Greer EL, Shi Y. Histone methylation: a dynamic mark in health, disease and inheritance. Nat Rev Genet. 2012;13(5):343-357 . https://doi.org/10.1038/nrg3173
41. Delmore JE, et al. BET bromodomain inhibition as a therapeutic strategy to target c-Myc. Cell. 2011;146:904-917. https://doi.org/10.1016/j.cell.2011.08.017
42. Stathis A, et al. Clinical response of carcinomas harboring the BRD4-NUT oncoprotein to BET inhibition. Cancer Discov. 2016;6:492-500. https://doi.org/10.1158/2159-8290.CD-15-1335
43. Amorim S, et al. Bromodomain inhibitor OTX015 in patients with acute leukemia and lymphoma. Nat Med. 2016;22:141-147. https://doi.org/10.1038/nm.4013
44. Shapiro GI, et al. Phase I studies of BET inhibitors in solid tumors. Clin Cancer Res. 2019;25:512-520. https://doi.org/10.1158/1078-0432.CCR-18-1548
45. Shu S, et al. Response and resistance to BET bromodomain inhibitors in triple-negative breast cancer. Nature. 2016;529:413-417. https://doi.org/10.1038/nature16508
46. Fong CY, et al. BET inhibitor resistance emerges from adaptive chromatin remodeling. Nat Commun. 2015;6:8512. https://doi.org/10.1038/ncomms9512
47. Peterlin BM, Price DH. Controlling the elongation phase of transcription with P-TEFb. Mol Cell. 2006;23(3):297-305. https://doi.org/10.1016/j.molcel.2006.06.014
48. Lu H, Xue Y, Yu GK, et al. Compensatory induction of MYC expression by sustained CDK9 inhibition via a BRD4-dependent mechanism. eLife. 2015;4:e06535. https://doi.org/10.7554/eLife.06535
49. Lücking U, Scholz A, Lienau P, et al. Identification of atuveciclib (BAY 1143572), a potent, selective, and orally active CDK9 inhibitor. ChemMedChem. 2017;12(21):1776-1793. https://doi.org/10.1002/cmdc.201700447
50. Cidado J, Boiko S, Proia T, et al. AZD4573 is a highly selective CDK9 inhibitor that suppresses MCL-1 and induces apoptosis in hematologic cancer models. Clin Cancer Res. 2020;26(4):922-934. https://doi.org/10.1158/1078-0432.CCR-19-1853
51. Tong WG, Chen R, Plunkett W, et al. Phase I and pharmacologic study of SNS-032, a potent inhibitor of CDK2, 7, and 9. J Clin Oncol. 2010;28(18):3015-3022. https://doi.org/10.1200/JCO.2009.25.8383
52. Whyte WA, Orlando DA, Hnisz D, et al. Master transcription factors and mediator establish super-enhancers at key cell identity genes. Cell. 2013;153(2):307-319. https://doi.org/10.1016/j.cell.2013.03.035
53. Allen BL, Taatjes DJ. The Mediator complex: a central integrator of transcription. Nat Rev Mol Cell Biol. 2015;16(3):155-166. https://doi.org/10.1038/nrm3951
54. Huang S, Hölzel M, Knijnenburg T, et al. MED12 controls the response to multiple cancer drugs through regulation of TGF-β receptor signaling. Cell. 2012;151(5):937-950. https://doi.org/10.1016/j.cell.2012.10.035
55. Pelish HE, Liau BB, Nitulescu II, et al. Mediator kinase inhibition further activates super-enhancer-associated genes in AML. Nature. 2015;526(7572):273-276. https://doi.org/10.1038/nature14962
56. Clarke PA, Ortiz-Ruiz MJ, TePoele R, et al. Assessing the mechanism and therapeutic potential of modulators of the human Mediator complex-associated kinases. Cancer Res. 2016;76(7):1876-1888. https://doi.org/10.1158/0008-5472.CAN-15-2323
57. Mounir Z, Korn JM, Westerling T, et al. ERG signaling in prostate cancer is driven through PRMT5-dependent transcriptional elongation. Cell Rep. 2016;17(12):3165-3178. https://doi.org/10.1016/j.celrep.2016.11.075
58. Heffeter P, Pape VF, Enyedy ÉA, et al. Antibody-drug conjugates based on RNA polymerase II inhibition for cancer therapy. Cancer Res. 2019;79(12):3126-3138. https://doi.org/10.1158/0008-5472.CAN-18-2954
59. Harlen KM, Churchman LS. The code and beyond: transcription regulation by the RNA polymerase II carboxy-terminal domain. Nat Rev Mol Cell Biol. 2017;18(4):263-273. https://doi.org/10.1038/nrm.2017.10
60. Lu X, Ning Z, Li Z, et al. Synergistic inhibition of super-enhancer-driven oncogenic transcription by BET and CDK9 inhibitors. Mol Cancer Ther. 2019;18(11):2054-2066. https://doi.org/10.1158/1535-7163.MCT-19-0312
61. Brock A, Chang H, Huang S. Non-genetic heterogeneity-a mutation-independent driving force for the somatic evolution of tumours. Nat Rev Genet. 2009;10(5):336-342. https://doi.org/10.1038/nrg2556
62. Bhadury J, Nilsson LM, Muralidharan SV, et al. BET and CDK9 inhibitors synergistically induce apoptosis in MYC-driven lymphomas. Leukemia. 2016;30(10):2031-2041. https://www.nature.com/articles/leu201510
63. Zwirner K, Sehouli J, Petry KU, et al. Circulating nucleosomes as epigenetic biomarkers in cancer. Clin Epigenetics. 2018;10:14. https://doi.org/10.1186/s13148-015-0139-4
64. Murtaza M, Dawson SJ, Tsui DWY, et al. Non-invasive analysis of acquired resistance to cancer therapy by sequencing of plasma DNA. Nature. 2013;497(7447):108-112. https://www.nature.com/articles/nature11168
65. Audia JE, Campbell RM. Histone modifications and cancer. Cold Spring Harb Perspect Biol. 2016;8(4):a019521. https://doi.org/10.1101/cshperspect.a019521
66. Bannister AJ, Kouzarides T. Regulation of chromatin by histone modifications. Cell Res. 2011;21(3):381-395. https://doi.org/10.1038/cr.2011.22
67. Choudhary C, et al. Lysine acetylation targets protein complexes and co-regulates major cellular functions. Science. 2009;325(5942):834-840. https://doi.org/10.1126/science.1175371
68. Iyer NG, et al. p300/CBP and cancer. Oncogene. 2004;23(24):4225-4231. https://doi.org/10.1038/sj.onc.1207118
69. Sapountzi V, Côté J. MYST-family histone acetyltransferases: beyond chromatin. Cell Mol Life Sci. 2011;68(7):1147-1156. https://doi.org/10.1007/s00018-010-0594-9
70. Baell JB, Miao W. Histone acetyltransferase inhibitors: where art thou? Future Med Chem. 2016;8(13):1525-1528. https://doi.org/10.4155/fmc-2016-0165
71. Kadoch C, Crabtree GR. Reversible disruption of epigenetic complexes by chemical and genetic perturbation. Nat Chem Biol. 2015;11(5):287-296. https://doi.org/10.1038/nchembio.1798
72. Sharma SV, Lee DY, Li B, et al. A chromatin-mediated reversible drug-tolerant state in cancer cell subpopulations. Cell. 2010;141(1):69-80. https://doi.org/10.1016/j.cell.2010.02.027
73. McKeown MR, Bradner JE. Therapeutic strategies to inhibit transcriptional drivers in cancer. Cell. 2014;158(1):26-41. https://doi.org/10.1016/j.cell.2014.05.024
74. Schwartz BE, et al. Differentiation of NUT carcinoma by epigenomic reprogramming. Cancer Res. 2011;71(7):2686-2696. https://doi.org/10.1158/0008-5472.CAN-10-3513
75. Bauer DE, et al. Clinical responses to BET inhibition in NUT carcinoma. J Clin Oncol. 2019;37(15):1207-1216. https://doi.org/10.1200/JCO.18.01833
76. West AC, Johnstone RW. New and emerging HDAC inhibitors for cancer treatment. J Clin Invest. 2014;124(1):30-39. https://doi.org/10.1172/JCI69738
77. Mohammad HP, et al. LSD1 inhibition induces differentiation and cell death in NUT midline carcinoma. Cancer Cell. 2015;28(1):57-69. https://doi.org/10.1016/j.ccell.2015.06.005
78. Maiques-Diaz A, Somervaille TCP. LSD1: biologic roles and therapeutic targeting. Epigenomics. 2016;8(8):1103-1116. https://doi.org/10.2217/epi-2016-0021
79. Fiskus W, et al. Pharmacodynamic biomarkers of LSD1 inhibition. Clin Cancer Res. 2014;20(6):1601-1612. https://doi.org/10.1158/1078-0432.CCR-13-2768
80. Sakamoto KM, et al. Protacs: chimeric molecules that target proteins to the Skp1-Cullin-F box complex for ubiquitination and degradation. Proc Natl Acad Sci USA. 2001;98(15):8554-8559. https://doi.org/10.1073/pnas.141230798
81. Lu J, et al. Hijacking the E3 ubiquitin ligase cereblon to efficiently target BRD4. Chem Biol. 2015;22(6):755-763. https://doi.org/10.1016/j.chembiol.2015.05.009
82. Zengerle M, Chan KH, Ciulli A. Selective small molecule induced degradation of the BET bromodomain protein BRD4. ACS Chem Biol. 2015;10(8):1770-1777. https://doi.org/10.1021/acschembio.5b00216
83. Winter GE, et al. Drug development: Phthalimide conjugation as a strategy for in vivo target protein degradation. Science. 2015;348(6241):1376-1381. https://doi.org/10.1126/science.aab1433
84. Bondeson DP, et al. Catalytic in vivo protein knockdown by small-molecule PROTACs. Nat Chem Biol. 2015;11(8):611-617. https://doi.org/10.1038/nchembio.1858
85. Sun X, Rao Y. PROTACs as potential therapeutic agents. Drug Discov Today. 2020;25(5): 1015-1027. https://doi.org/10.1016/j.drudis.2020.03.026
86. Stathis A, Bertoni F. BET proteins as targets for anticancer treatment. Cancer Discov. 2018;8(1):24-36. https://doi.org/10.1158/2159-8290.CD-17-0601
87. Flavahan WA, Gaskell E, Bernstein BE. Epigenetic plasticity and the hallmarks of cancer. Science. 2017;357(6348):eaal2380. https://doi.org/10.1126/science.aal2380
88. Hinohara K, Polyak K. Intratumoral heterogeneity: more than just mutations. Trends Cell Biol. 2019;29(7):569-579. https://doi.org/10.1016/j.tcb.2019.03.003
89. Mansour MR, et al. Oncogene regulation by dynamic enhancer-promoter associations. Nature. 2014;514(7522):381-385. https://doi.org/10.1038/nature13794
90. Hyman DM, Taylor BS, Baselga J. Implementing genome-driven oncology. Cell. 2017;168(4):584-599. https://doi.org/10.1016/j.cell.2016.12.015
91. Dawson MA. The cancer epigenome: concepts, challenges, and therapeutic opportunities. Science. 2017;355(6330):1147-1152. https://doi.org/10.1126/science.aam7304
92. Flavahan WA, et al. Epigenetic plasticity and the hallmarks of cancer. Science. 2017;357(6348):eaal2380. https://doi.org/10.1126/science.aal2380
93. Feinberg AP, Koldobskiy MA, Göndör A. Epigenetic modulators, modifiers and mediators in cancer aetiology and progression. Nat Rev Genet. 2016;17(5):284-299. https://doi.org/10.1038/nrg.2016.13
94. French CA. NUT carcinoma: clinicopathologic features, pathogenesis, and treatment. Pathol Int. 2018;68(11):583-595. https://doi.org/10.1111/pin.12727
95. Dunn GP, et al. Cancer immunoediting: from immunosurveillance to tumor escape. Nat Immunol. 2002;3(11):991-998. https://doi.org/10.1038/ni1102-991
96. Binnewies M, et al. Understanding the tumor immune microenvironment. Nat Med. 2018;24(5):541-550. https://doi.org/10.1038/s41591-018-0014-x
97. Chiappinelli KB, et al. Inhibiting DNA methylation causes an interferon response in cancer via dsRNA including endogenous retroviruses. Cell. 2015;162(5):974-986. https://doi.org/10.1016/j.cell.2015.07.011
98. Topper MJ, et al. Epigenetic therapy ties MYC depletion to reversing immune evasion and treating lung cancer. Cell. 2017;171(6):1284-1300. https://doi.org/10.1016/j.cell.2017.10.022
99. Jones PA, Ohtani H, Chakravarthy A, De Carvalho DD. Epigenetic therapy in immune-oncology. Nat Rev Cancer. 2019;19(3):151-161. https://doi.org/10.1038/s41568-019-0109-9
100. Stone ML, et al. Epigenetic therapy activates type I interferon signaling in murine ovarian cancer to reduce immunosuppression and tumor burden. Proc Natl Acad Sci USA. 2017;114(51):E10981-E10990. https://doi.org/10.1073/pnas.1712514114
101. Drilon A, Laetsch TW, Kummar S, et al. Efficacy of larotrectinib in TRK fusion-positive cancers in adults and children. N Engl J Med. 2018;378(8):731-739. https://doi.org/10.1056/NEJMoa1714448
102. Park JJH, Siden E, Zoratti MJ, et al. Systematic review of basket trials, umbrella trials, and platform trials: a landscape analysis of master protocols. Trials. 2019;20:572. https://doi.org/10.1186/s13063-019-3664-1
103. Woodcock J, LaVange LM. Master protocols to study multiple therapies, multiple diseases, or both. N Engl J Med. 2017;377(1):62-70. https://doi.org/10.1056/NEJMra1510062
104. U.S. Food and Drug Administration. Rare diseases: common issues in drug development guidance for industry. FDA; 2019. https://www.fda.gov/media/120091/download
105. Shapiro GI, LoRusso P, Dowlati A, et al. Pharmacokinetic and pharmacodynamic considerations in the development of epigenetic therapies. Clin Cancer Res. 2019;25(17):512-520. https://pubmed.ncbi.nlm.nih.gov/?
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