Skip to main content
SpringerLink
Log in

Targeting Chromatin-Mediated Transcriptional Control of Gene Expression in Non-Small Cell Lung Cancer Therapy: Preclinical Rationale and Clinical Results

  • Review Article
  • Published:
Drugs Aims and scope Submit manuscript

Abstract

Targeting chromatin-mediated transcriptional control of gene expression is nowadays considered a promising new strategy, transcending conventional anticancer therapy. As a result, molecules acting as DNA demethylating agents or histone deacetylase inhibitors (HDACi) have entered the clinical arena in the last decade. Given the evidence suggesting that epigenetic regulation is significantly involved in lung cancer development and progression, the potential of epigenetically active compounds to modulate gene expression and reprogram cancer cells to a less aggressive phenotype is, at present, a promising strategy. Accordingly, a large number of compounds that interact with the epigenetic machinery of gene expression regulation are now being developed and tested as potential antitumor agents, either alone or in combination with standard therapy. The preclinical rationale and clinical data concerning the pharmacological modulation of chromatin organization in non-small cell lung cancer (NSCLC) is described in this review. Although preclinical data suggest that a pharmacological treatment targeting the epigenetic machinery has relevant activity over the neoplastic phenotype of NSCLC cells, clinical results are disappointing, leading only to short periods of disease stabilization in NSCLC patients. This evidence calls for a significant rethinking of strategies for an effective epigenetic therapy of NSCLC. The synergistic effect of concurrent epigenetic therapies, use at low doses, the priming of current treatments with previous epigenetic drugs, and the selection of clinical trial populations based on epigenetic biomarkers/signatures appear to be the cornerstones of a mature therapeutic strategy aiming to establish new regimens for reprogramming malignant cells and improving the clinical history of affected patients.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

References

  1. Jemal A, Bray F, Center MM, et al. Global cancer statistics. CA Cancer J Clin. 2011;61(2):69–90.

    Article  PubMed  Google Scholar 

  2. Vansteenkiste J, De Ruysscher D, Eberhardt WE, et al. Early and locally advanced non-small-cell lung cancer (NSCLC): ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2013;24(Suppl 6):vi89–98.

    Article  PubMed  Google Scholar 

  3. Reck M, Heigener DF, Mok T, et al. Management of non-small-cell lung cancer: recent developments. Lancet. 2013;382(9893):709–19.

    Article  CAS  PubMed  Google Scholar 

  4. Soria JC, Mok TS, Cappuzzo F, Jänne PA. EGFR-mutated oncogene-addicted non-small cell lung cancer: current trends and future prospects. Cancer Treat Rev. 2012;38(5):416–30.

    Article  CAS  PubMed  Google Scholar 

  5. Yang JC, Wu Y, Schuler M, et al. Afatinib versus cisplatin-based chemotherapy for EGFR mutation-positive lung adenocarcinoma (LUX-Lung 3 and LUX-Lung 6): analysis of overall survival data from two randomised, phase 3 trials. Lancet Oncol. 2015;16(7):830–8.

    Article  CAS  PubMed  Google Scholar 

  6. Reck M, Popat S, Reinmuth N, et al. Metastatic non-small-cell lung cancer (NSCLC): ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2014;25(Suppl 3):iii27–39.

    Article  PubMed  Google Scholar 

  7. Capelletto E, Novello S. Emerging new agents for the management of patients with non-small cell lung cancer. Drugs. 2012;72(Suppl 1):37–52.

    Article  CAS  PubMed  Google Scholar 

  8. Cameron L, Solomon B. Treatment of ALK-rearranged non-small cell lung cancer: recent progress and future directions. Drugs. 2015;75(10):1059–70.

    Article  CAS  PubMed  Google Scholar 

  9. Brahmer J, Reckamp KL, Baas P, et al. Nivolumab versus docetaxel in advanced squamous-cell non-small-cell lung cancer. N Engl J Med. 2015;373(2):123–35.

    Article  CAS  PubMed  Google Scholar 

  10. Paz-Ares L, Horn L, Borghaei H, et al. Phase III, randomized trial (CheckMate 057) of nivolumab (NIVO) versus docetaxel (DOC) in advanced non-squamous cell (non-SQ) non-small cell lung cancer (NSCLC). J Clin Oncol. 2015;33(15):LBA109.

    Google Scholar 

  11. Garon EB, Rizvi NA, Hui R, et al. Pembrolizumab for the treatment of non–small-cell lung cancer. N Engl J Med. 2015;372(21):2018–28.

    Article  PubMed  Google Scholar 

  12. Wen J, Fu J, Zhang W, Guo M. Genetic and epigenetic changes in lung carcinoma and their clinical implications. Mod Pathol. 2011;24(7):932–43.

    Article  PubMed  Google Scholar 

  13. Pasini A, Paganelli G, Tesei, et al. Specific biomarkers are associated with docetaxel and gemcitabine-resistant NSCLC cell lines. Transl Oncol. 2012;5(6):461–8.

    Article  PubMed Central  PubMed  Google Scholar 

  14. Brzeziańska E, Dutkowska A, Antczak A. The significance of epigenetic alterations in lung carcinogenesis. Mol Biol Rep. 2013;40(1):309–25.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  15. Jones PA, Baylin SB. The epigenomics of cancer. Cell. 2007;128(4):683–92.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  16. Heller G, Zielinski CC, Zöchbauer-Müller S. Lung cancer: from single-gene methylation to methylome profiling. Cancer Metastasis Rev. 2010;29(1):95–107.

    Article  CAS  PubMed  Google Scholar 

  17. Gomperts BN, Spira A, Massion PP, et al. Evolving concepts in lung carcinogenesis. Semin Respir Crit Care Med. 2011;32(1):32–43.

    Article  PubMed Central  PubMed  Google Scholar 

  18. Belinsky SA. Gene-promoter hypermethylation as a biomarker in lung cancer. Nat Rev Cancer. 2004;4(9):707–17.

    Article  CAS  PubMed  Google Scholar 

  19. Belinsky SA, Liechty KC, Gentry FD, et al. Promoter hypermethylation of multiple genes in sputum precedes lung cancer incidence in a high-risk cohort. Cancer Res. 2006;66(6):3338–44.

    Article  CAS  PubMed  Google Scholar 

  20. Liloglou T, Bediaga NG, Brown BR, Field JK, Davies MP. Epigenetic biomarkers in lung cancer. Cancer Lett. 2014;342(2):200–12.

    Article  CAS  PubMed  Google Scholar 

  21. Toyooka S, Suzuki M, Maruyama R, et al. The relationship between aberrant methylation and survival in non-small-cell lung cancers. Br J Cancer. 2004;91(4):771–4.

    PubMed Central  CAS  PubMed  Google Scholar 

  22. Kim DH, Kim JS, Ji YI, et al. Hypermethylation of RASSF1A promoter is associated with the age at starting smoking and a poor prognosis in primary non-small cell lung cancer. Cancer Res. 2003;63(13):3743–6.

    CAS  PubMed  Google Scholar 

  23. Brock MV, Hooker CM, Ota-Machida E, et al. DNA methylation markers and early recurrence in stage I lung cancer. N Engl J Med. 2008;358(11):1118–28.

    Article  CAS  PubMed  Google Scholar 

  24. Weber B, Stresemann C, Brueckner B, Lyko F. Methylation of human microRNA genes in normal and neoplastic cells. Cell Cycle. 2007;6(9):1001–5.

    Article  CAS  PubMed  Google Scholar 

  25. Lujambio A, Ropero S, Ballestar E, et al. Genetic unmasking of an epigenetically silenced microRNA in human cancer cells. Cancer Res. 2007;67(4):1424–9.

    Article  CAS  PubMed  Google Scholar 

  26. Rhee I, Jair KW, Yen RW, et al. CpG methylation is maintained in human cancer cells lacking DNMT1. Nature. 2000;404:1003–7.

    Article  CAS  PubMed  Google Scholar 

  27. Okano M, Xie S, Li E. Cloning and characterization of a family of novel mammalian DNA (cytosine-5) methyltransferases. Nat Genet. 1998;19(3):219–20.

    Article  CAS  PubMed  Google Scholar 

  28. Kim H, Kwon YM, Kim JS, et al. Elevated mRNA levels of DNA methyltransferase-1 as an independent prognostic factor in primary nonsmall cell lung cancer. Cancer. 2006;107(5):1042–9.

    Article  CAS  PubMed  Google Scholar 

  29. Lin RK, Hsu HS, Chang JW, et al. Alteration of DNA methyltransferases contributes to 5’CpG methylation and poor prognosis in lung cancer. Lung Cancer. 2007;55(2):205–13.

    Article  PubMed  Google Scholar 

  30. Jones PL, Veenstra GJ, Wade PA, et al. Methylated DNA and MeCP2 recruit histone deacetylase to repress transcription. Nat Genet. 1998;19(2):187–91.

    Article  CAS  PubMed  Google Scholar 

  31. Nan X, Ng HH, Johnson CA, Laherty CD, et al. Transcriptional repression by the methyl-CpG-binding protein MeCP2 involves a histone deacetylase complex. Nature. 1999;393(6683):386–9.

    Google Scholar 

  32. Fuks F, Hurd PJ, Wolf D, Nan X, Bird AP, Kouzarides T. The methyl-CpG-binding protein MeCP2 links DNA methylation to histone methylation. J Biol Chem. 2003;278(6):4035–40.

    Article  CAS  PubMed  Google Scholar 

  33. Vaissière T, Sawan C, Herceg Z. Epigenetic interplay between histone modifications and DNA methylation in gene silencing. Mutat Res. 2008;659(1–2):40–8.

    Article  PubMed  CAS  Google Scholar 

  34. Seligson DB, Horvath S, McBrian MA, et al. Global levels of histone modifications predict prognosis in different cancers. Am J Pathol. 2009;174(5):1619–28.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  35. Song JS, Kim YS, Kim DK, et al. Global histone modification pattern associated with recurrence and disease-free survival in non-small cell lung cancer patients. Pathol Int. 2012;62(3):182–90.

    Article  PubMed  Google Scholar 

  36. Marchion D, Münster P. Development of histone deacetylase inhibitors for cancer treatment. Expert Rev Anticancer Ther. 2007;7(4):583–98.

    Article  CAS  PubMed  Google Scholar 

  37. Sasaki H, Moriyama S, Nakashima Y, et al. Histone deacetylase 1 mRNA expression in lung cancer. Lung Cancer. 2004;46(2):171–8.

    Article  PubMed  Google Scholar 

  38. Jeon HS, Lee SY, Lee EJ, et al. Combining microRNA-449a/b with a HDAC inhibitor has a synergistic effect on growth arrest in lung cancer. Lung Cancer. 2012;76(2):171–6.

    Article  PubMed  Google Scholar 

  39. Minamiya Y, Ono T, Saito H, et al. Strong expression of HDAC3 correlates with a poor prognosis in patients with adenocarcinoma of the lung. Tumor Biol. 2010;31(5):533–9.

    Article  CAS  Google Scholar 

  40. Osada H, Tatematsu Y, Saito H, et al. Reduced expression of class II histone deacetylase genes is associated with poor prognosis in lung cancer patients. Int J Cancer. 2004;112(1):26–32.

    Article  CAS  PubMed  Google Scholar 

  41. Hudlebusch HR, Santoni-Rugiu E, Simon R, et al. The histone methyltransferase and putative oncoprotein MMSET is overexpressed in a large variety of human tumors. Clin Cancer Res. 2011;17(9):2919–33.

    Article  CAS  PubMed  Google Scholar 

  42. Kikuchi J, Kinoshita I, Shimizu Y, et al. Distinctive expression of the polycomb group proteins Bmi1 polycomb ring finger oncogene and enhancer of zeste homolog 2 in nonsmall cell lung cancers and their clinical and clinicopathologic significance. Cancer. 2010;116(12):3015–24.

    Article  CAS  PubMed  Google Scholar 

  43. Labbé RM, Holowatyj A, Yang ZQ. Histone lysine demethylase (KDM) subfamily 4: structures, functions and therapeutic potential. Am J Transl Res. 2013;6(1):1–15.

    PubMed Central  PubMed  Google Scholar 

  44. Tsukada Y, Fang J, Erdjument-Bromage H, et al. Histone demethylation by a family of JmjC domain-containing proteins. Nature. 2006;439:811–6.

    Article  CAS  PubMed  Google Scholar 

  45. Wagner KW, Alam H, Dhar SS, et al. KDM2A promotes lung tumorigenesis by epigenetically enhancing ERK1/2 signaling. J Clin Invest. 2013;123(12):5231–46.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  46. Dhar SS, Alam H, Li N, et al. Transcriptional repression of histone deacetylase 3 by the histone demethylase KDM2A is coupled to tumorigenicity of lung cancer cells. J Biol Chem. 2014;289(11):7483–96.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  47. Berry WL, Janknecht R. KDM4/JMJD2 histone demethylases: epigenetic regulators in cancer cells. Cancer Res. 2013;73(10):2936–42.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  48. Kogure M, Takawa M, Cho HS, et al. D eregulation of the histone demethylase JMJD2A is involved in human carcinogenesis through regulation of the G(1)/S transition. Cancer Lett. 2013;336(1):76–84.

    Article  CAS  PubMed  Google Scholar 

  49. Bannister AJ, Kouzarides T. Regulation of chromatin by histone modifications. Cell Res. 2011;21(3):381–95.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  50. Di Lorenzo A, Bedford MT. Histone arginine methylation. FEBS Lett. 2011;585(13):2024–31.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  51. Molina-Serrano D, Schiza V, Kirmizis A. Cross-talk among epigenetic modifications: lessons from histone arginine methylation. Biochem Soc Trans. 2013;41(3):751–9.

    Article  CAS  PubMed  Google Scholar 

  52. Yoshimatsu M, Toyokawa G, Hayami S, et al. Dysregulation of PRMT1 and PRMT6, type I arginine methyltransferases, is involved in various types of human cancers. Int J Cancer. 2011;128(3):562–73.

    Article  CAS  PubMed  Google Scholar 

  53. Zhang J, Ni SS, Zhao WL, Dong XC, Wang JL. High expression of JMJD6 predicts unfavorable survival in lung adenocarcinoma. Tumor Biol. 2013;34(4):2397–401.

    Article  CAS  Google Scholar 

  54. Patel DJ, Wang Z. Readout of epigenetic modifications. Annu Rev Biochem. 2013;82:81–118.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Shimamura T, Chen Z, Soucheray M, et al. Efficacy of BET bromodomain inhibition in Kras-mutant non-small cell lung cancer. Clin Cancer Res. 2013;19(22):6183–92.

    Article  CAS  PubMed  Google Scholar 

  56. Rodríguez-Paredes M, Esteller M. Cancer epigenetics reaches mainstream oncology. Nat Med. 2011;17(3):330–9.

    Article  PubMed  CAS  Google Scholar 

  57. Hazeldine S, Pachaiyappan B, Steinbergs N, et al. Low molecular weight amidoximes that act as potent inhibitors of lysine-specific demethylase 1. J Med Chem. 2012;55(17):7378–91.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  58. Pasini A, Caldarera CM, Giordano E. Chromatin remodeling by polyamines and polyamine analogues. Amino Acids. 2014;46(3):595–603.

    Article  CAS  PubMed  Google Scholar 

  59. Treppendahl MB, Kristensen LS, Grønbæk K. Predicting response to epigenetic therapy. J Clin Invest. 2014;124(1):47–55.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  60. Baylin SB. DNA methylation and gene silencing in cancer. Nat Clin Pract Oncol. 2005;2(Suppl 1):S4–11.

    Article  CAS  PubMed  Google Scholar 

  61. Carafa V, Miceli M, Altucci L, Nebbioso A. Histone deacetylase inhibitors: a patent review (2009–2011). Expert Opin Ther Pat. 2013;23(1):1–17.

    Article  CAS  PubMed  Google Scholar 

  62. Bolden JE, Shi W, Jankowski K, et al. HDAC inhibitors induce tumor-cell-selective pro-apoptotic transcriptional responses. Cell Death Dis. 2013;4:e519. doi:10.1038/cddis.2013.9.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  63. Lane AA, Chabner BA. Histone deacetylase inhibitors in cancer therapy. J Clin Oncol. 2009;27(32):5459–68.

    Article  CAS  PubMed  Google Scholar 

  64. Piekarz RL, Frye R, Turner M, et al. Phase II multi-institutional trial of the histone deacetylase inhibitor romidepsin as monotherapy for patients with cutaneous T-cell lymphoma. J Clin Oncol. 2009;27(32):5410–7.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  65. Duvic M, Talpur R, Ni X, et al. Phase 2 trial of oral vorinostat (suberoylanilide hydroxamic acid, SAHA) for refractory cutaneous T-cell lymphoma (CTCL). Blood. 2007;109(1):31–9 (published erratum appears in Blood. 2007;109(12):5086).

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  66. Seo SK, Jin HO, Woo SH, et al. Histone deacetylase inhibitors sensitize human non-small cell lung cancer cells to ionizing radiation through acetyl p53-mediated c-myc down-regulation. J Thorac Oncol. 2011;6(8):1313–9.

    Article  PubMed  Google Scholar 

  67. Geng L, Cuneo KC, Fu A, et al. Histone deacetylase (HDAC) inhibitor LBH589 increases duration of gamma-H2AX foci and confines HDAC4 to the cytoplasm in irradiated non-small cell lung cancer. Cancer Res. 2006;66(23):11298–304.

    Article  CAS  PubMed  Google Scholar 

  68. Zhang F, Zhang T, Teng ZH, et al. Sensitization to gamma-irradiation-induced cell cycle arrest and apoptosis by the histone deacetylase inhibitor trichostatin A in non-small cell lung cancer (NSCLC) cells. Cancer Biol Ther. 2009;8(9):823–31.

    Article  CAS  PubMed  Google Scholar 

  69. Hehlgans S, Storch K, Lange I, Cordes N. The novel HDAC inhibitor NDACI054 sensitizes human cancer cells to radiotherapy. Radiother Oncol. 2013;109(1):126–32.

    Article  CAS  PubMed  Google Scholar 

  70. Zuco V, DeCesare M, Cincinelli R, et al. Synergistic antitumor effects of novel HDAC inhibitors and paclitaxel in vitro and in vivo. PLoS One. 2013;6:e29085.

    Article  CAS  Google Scholar 

  71. Tesei A, Brigliadori G, Carloni S, et al. Organosulfur derivatives of the HDAC inhibitor valproic acid sensitize human lung cancer cell lines to apoptosis and to cisplatin cytotoxicity. J Cell Physiol. 2012;227(10):3389–96.

    Article  CAS  PubMed  Google Scholar 

  72. Owonikoko TK, Ramalingam SS, Kanterewicz B, et al. Vorinostat increases carboplatin and paclitaxel activity in non-small-cell lung cancer cells. Int J Cancer. 2010;126(3):743–55.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  73. Del Bufalo D, Desideri M, De Luca T, et al. Histone deacetylase inhibition synergistically enhances pemetrexed cytotoxicity through induction of apoptosis and autophagy in non-small cell lung cancer. Mol Cancer. 2014;13:230.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  74. Sharma SV, Lee DY, Li B, et al. A chromatin-mediated reversible drug tolerant state in cancer cell subpopulations. Cell. 2010;141:69–80.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  75. Lee TG, Jeong EH, Kim SY, Kim HR, Kim CH. The combination of irreversible EGFR TKIs and SAHA induces apoptosis and autophagy-mediated cell death to overcome acquired resistance in EGFR T790M-mutated lung cancer. Int J Cancer. 2015;136(11):2717–29.

    Article  CAS  PubMed  Google Scholar 

  76. Zhang W, Peyton M, Xie Y, et al. Histone deacetylase inhibitor romidepsin enhances anti-tumor effect of erlotinib in non-small cell lung cancer (NSCLC) cell lines. J Thorac Oncol. 2009;4(2):161–6.

    Article  PubMed Central  PubMed  Google Scholar 

  77. Belinsky SA, Grimes MJ, Picchi MA, et al. Combination therapy with Vidaza and entinostat suppresses tumor growth and reprograms the epigenome in an orthotopic lung cancer model. Cancer Res. 2011;71:454–62.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  78. Zhu WG, Lakshmanan RR, Beal MD, Otterson GA. DNA methyltransferase inhibition enhances apoptosis induced by histone deacetylase inhibitors. Cancer Res. 2001;61:1327–33.

    CAS  PubMed  Google Scholar 

  79. Li XY, Wu JZ, Cao HX, et al. Blockade of DNA methylation enhances the therapeutic effect of gefitinib in non-small cell lung cancer cells. Oncol Rep. 2013;29(5):1975–82.

    CAS  PubMed  Google Scholar 

  80. Singh T, Prasad R, Katiyar SK. Inhibition of class I histone deacetylases in non-small cell lung cancer by honokiol leads to suppression of cancer cell growth and induction of cell death in vitro and in vivo. Epigenetics. 2013;8:54–65.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  81. Tang YA, Wen WL, Chang JW, et al. A novel histone deacetylase inhibitor exhibits antitumor activity via apoptosis induction, F-actin disruption and gene acetylation in lung cancer. PLoS One. 2010;14:e12417.

    Article  CAS  Google Scholar 

  82. Mateen S, Raina K, Agarwal C, et al. Silibinin synergizes with histone deacetylase and DNA methyltransferase inhibitors in upregulating E-cadherin expression together with inhibition of migration and invasion of human non-small cell lung cancer cells. J Pharmacol Exp Ther. 2013;345(2):206–14.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  83. Kikuchi J, Takashina T, Kinoshita I, et al. Epigenetic therapy with 3-deazaneplanocin A, an inhibitor of the histone methyltransferase EZH2, inhibits growth of non-small cell lung cancer cells. Lung Cancer. 2012;78(2):138–43.

    Article  PubMed Central  PubMed  Google Scholar 

  84. Lee JK, Kim KC. DZNep, inhibitor of S-adenosylhomocysteine hydrolase, down-regulates expression of SETDB1 H3K9me3 HMTase in human lung cancer cells. Biochem Biophys Res Commun. 2013;438(4):647–52.

    Article  CAS  PubMed  Google Scholar 

  85. Rao M, Chinnasamy N, Hong JA, et al. Inhibition of histone lysine methylation enhances cancer-testis antigen expression in lung cancer cells: implications for adoptive immunotherapy of cancer. Cancer Res. 2011;71(12):4192–204.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  86. Fillmore CM, Xu C, Desai PT, et al. EZH2 inhibition sensitizes BRG1 and EGFR mutant lung tumours to TopoII inhibitors. Nature. 2015;520(7546):239–42.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  87. Lv T, Yuan D, Miao X, et al. Over-expression of LSD1 promotes proliferation, migration and invasion in non-small cell lung cancer. PLoS One. 2012;7(4):e35065.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  88. Wang L, Chang J, Varghese D, et al. A small molecule modulates Jumonji histone demethylase activity and selectively inhibits cancer growth. Nat Commun. 2013;4:2035.

    PubMed Central  PubMed  Google Scholar 

  89. Lockwood WW, Zejnullahu K, Bradner JE, Varmus H. Sensitivity of human lung adenocarcinoma cell lines to targeted inhibition of BET epigenetic signaling proteins. Proc Natl Acad Sci USA. 2012;109(47):19408–13.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  90. Momparler RL, Bouffard DY, Momparler LF, et al. Pilot phase I-II study on 5-aza- 20-deoxycytidine (decitabine) in patients with metastatic lung cancer. Anticancer Drugs. 1997;8:358–68.

    Article  CAS  PubMed  Google Scholar 

  91. Schrump DS, Fischette MR, Nguyen DM, et al. Phase I study of decitabine-mediated gene expression in patients with cancers involving the lung, esophagus, or pleura. Clin Cancer Res. 2006;12:5777–85.

    Article  CAS  PubMed  Google Scholar 

  92. Reid T, Valone F, Lipera W, et al. Phase II trial of the histone deacetylase inhibitor pivaloyloxymethyl butyrate (Pivanex, AN-9) in advanced non-small cell lung cancer. Lung Cancer. 2004;45(3):381–6.

    Article  PubMed  Google Scholar 

  93. Schrump DS, Fischette MR, Nguyen DM, et al. Clinical and molecular responses in lung cancer patients receiving Romidepsin. Clin Cancer Res. 2008;14(1):188–98.

    Article  CAS  PubMed  Google Scholar 

  94. Traynor AM, Dubey S, Eickhoff JC, et al. Vorinostat (NSC#701852) in patients with relapsed non-small cell lung cancer: a Wisconsin Oncology Network phase II study. J Thorac Oncol. 2009;4:522–6.

    Article  PubMed Central  PubMed  Google Scholar 

  95. Ryan QC, Headlee D, Acharya M, et al. Phase I and pharmacokinetic study of MS-275, a histone deacetylase inhibitor, in patients with advanced and refractory solid tumors or lymphoma. J Clin Oncol. 2005;23:3912–22.

    Article  CAS  PubMed  Google Scholar 

  96. Vansteenkiste J, VanCutsem E, Dumez H, et al. Early phase II trial of oral vorinostat in relapsed or refractory breast, colorectal, or non-small cell lung cancer. Invest New Drugs. 2008;26:483–8.

    Article  CAS  PubMed  Google Scholar 

  97. Fukutomi A, Hatake K, Matsui K, et al. A phase I study of oral panobinostat (LBH589) in Japanese patients with advanced solid tumors. Invest New Drugs. 2012;30(3):1096–106.

    Article  CAS  PubMed  Google Scholar 

  98. Azad N, Zahnow CA, Rudin CM, Baylin SB. The future of epigenetic therapy in solid tumors: lessons from the past. Nat Rev Clin Oncol. 2013;10(5):256–66.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  99. Tsai HC, Li H, Van Neste L, et al. Transient low doses of DNA-demethylating agents exert durable antitumor effects on hematological and epithelial tumor cells. Cancer Cell. 2012;21(3):430–46.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  100. Forde PM, Brahmer JR, Kelly RJ. New strategies in lung cancer: epigenetic therapy for non-small cell lung cancer. Clin Cancer Res. 2014;20(9):2244–8.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  101. Zarogoulidis P, Chatzaki E, Porpodis K, et al. Inhaled chemotherapy in lung cancer: future concept of nanomedicine. Int J Nanomedicine. 2012;7:1551–15572.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  102. Sharma SK, Hazeldine S, Crowley ML, et al. Polyamine-based small molecule epigenetic modulators. Medchemcomm. 2012;3(1):14–21.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  103. Wang L, Xiang S, Williams KA, et al. Depletion of HDAC6 enhances cisplatin-induced DNA damage and apoptosis in non-small cell lung cancer cells. PLoS One. 2012;7(9):e44265.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  104. Belinsky SA, Klinge DM, Stidley CA, et al. Inhibition of DNA methylation and histone deacetylation prevents murine lung cancer. Cancer Res. 2003;63:7089–93.

    CAS  PubMed  Google Scholar 

  105. Chu BF, Karpenko MJ, Liu Z, et al. Phase I study of 5-aza-2′-deoxycytidine in combination with valproic acid in non-small cell lung cancer. Cancer Chemother Pharmacol. 2013;71:115–21.

    Article  CAS  PubMed  Google Scholar 

  106. Candelaria M, Gallardo-Rincón D, Arce C, et al. A phase II study of epigenetic therapy with hydralazine and magnesium valproate to overcome chemotherapy resistance in refractory solid tumors. Ann Oncol. 2007;18(9):1529–38.

    Article  CAS  PubMed  Google Scholar 

  107. Lin J, Gilbert J, Rudek MA, et al. A phase I dose-finding study of 5-azacytidine in combination with sodium phenylbutyrate in patients with refractory solid tumors. Clin Cancer Res. 2009;15(19):6241–9.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  108. Stathis A, Hotte SJ, Chen EX, et al. Phase I study of decitabine in combination with vorinostat in patients with advanced solid tumors and non-Hodgkin’s lymphomas. Clin Cancer Res. 2011;17(6):1582–90.

    Article  CAS  PubMed  Google Scholar 

  109. Juergens RA, Wrangle J, Vendetti FP, et al. Combination epigenetic therapy has efficacy in patients with refractory advanced non-small cell lung cancer. Cancer Discov. 2011;1(7):598–607.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  110. Papavassiliou KA, Papavassiliou AG. Histone deacetylases inhibitors: conjugation to other anti-tumor pharmacophores provides novel tools for cancer treatment. Expert Opin Investig Drugs. 2014;23(3):291–4.

    Article  CAS  PubMed  Google Scholar 

  111. Zhang X, Su M, Chen Y, et al. The design and synthesis of a new class of RTK/HDAC dual-targeted inhibitors. Molecules. 2013;18(6):6491–503.

    Article  CAS  PubMed  Google Scholar 

  112. Ramalingam SS, Maitland ML, Frankel P, et al. Carboplatin and paclitaxel in combination with either vorinostat or placebo for first line therapy of advanced non-small cell lung cancer. J Clin Oncol. 2010;28:56–62.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  113. Belani C, Ramalingam S, Kalemkerian G, et al. Randomised, double-blind phase II–III study of first line paclitaxel (P) plus carboplatin (C) in combination with vorinostat or placebo in patients with advanced non-small-cell lung cancer (NSCLC) [abstract no. 0-9007]. Eur J Cancer Suppl. 2009;7(2):507.

    Article  Google Scholar 

  114. Heyn H, Esteller M. DNA methylation profiling in the clinic: applications and challenges. Nat Rev Genet. 2012;13:679–92.

    Article  CAS  PubMed  Google Scholar 

  115. Govindan R, Ding L, Griffith M, et al. Genomic landscape of non-small cell lung cancer in smokers and never-smokers. Cell. 2012;150:1121–34.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  116. Paz-Ares LG, de Marinis F, Dediu M, et al. PARAMOUNT: final overall survival results of the phase III study of maintenance pemetrexed versus placebo immediately after induction treatment with pemetrexed plus cisplatin for advanced nonsquamous non–small-cell lung cancer. J Clin Oncol. 2013;31(23):2895–902.

    Article  CAS  PubMed  Google Scholar 

  117. Walter K, Holcomb T, Januario T, et al. Discovery and development of DNA methylation-based biomarkers for lung cancer. Epigenomics. 2014;6(1):59–72.

    Article  CAS  PubMed  Google Scholar 

  118. Sandoval J, Mendez-Gonzalez J, Nadal E, et al. A prognostic DNA methylation signature for stage I non–small-cell lung cancer. J Clin Oncol. 2013;31(32):4140–7.

    Article  PubMed  Google Scholar 

  119. Wrangle J, Wang W, Koch A, et al. Alterations of immune response of non-small cell lung cancer with Azacytidine. Oncotarget. 2013;4(11):2067–79.

    Article  PubMed Central  PubMed  Google Scholar 

  120. Pauer LR, Olivares J, Cunningham C, et al. Trial with CI-994 paclitaxel and/or carboplatin. Cancer Invest. 2004;22(6):886–96.

    Article  CAS  PubMed  Google Scholar 

  121. Schneider BJ, Kalemkerian GP, Bradley D, et al. Phase I study of vorinostat (suberoylanilide hydroxamic acid, NSC 701852) in combination with docetaxel in patients with advanced and relapsed solid malignancies. Invest New Drugs. 2012;30(1):249–57.

    Article  CAS  PubMed  Google Scholar 

  122. Witta SE, Jotte RM, Konduri K, et al. Randomized phase II trial of erlotinib with and without entinostat in patients with advanced non-small-cell lung cancer who progressed on prior chemotherapy. J Clin Oncol. 2012;30(18):2248–55.

    Article  CAS  PubMed  Google Scholar 

  123. Reguart N, Rosell R, Cardenal F, et al. Phase I/II trial of vorinostat (SAHA) and erlotinib for non-small cell lung cancer (NSCLC) patients with epidermal growth factor receptor (EGFR) mutations after erlotinib progression. Lung Cancer. 2014;84(2):161–7.

    Article  PubMed  Google Scholar 

  124. Dasari A, Gore L, Messersmith WA, et al. A phase I study of sorafenib and vorinostat in patients with advanced solid tumors with expanded cohorts in renal cell carcinoma and non-small cell lung cancer. Invest New Drugs. 2013;31(1):115–25.

    Article  CAS  PubMed  Google Scholar 

  125. Gray JE, Haura E, Chiappori A, et al. A Phase i, pharmacokinetic, and pharmacodynamic study of panobinostat, an HDAC inhibitor, combined with erlotinib in patients with advanced aerodigestive tract tumors. Clin Cancer Res. 2014;20(6):1644–55.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  126. Jones DR, Moskaluk CA, Gillenwater HH, et al. Phase I trial of induction histone deacetylase and proteasome inhibition followed by surgery in non-small cell lung cancer. J Thorac Oncol. 2012;7:1683–90.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  127. Schelman WR, Traynor AM, Holen KD, et al. A phase I study of vorinostat in combination with bortezomib in patients with advanced malignancies. Invest New Drugs. 2013;31(6):1539–46.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  128. Hoang T, Campbell TC, Zhang C, et al. Vorinostat and bortezomib as third-line therapy in patients with advanced non-small cell lung cancer: a Wisconsin Oncology Network Phase II study. Invest New Drugs. 2014;32(1):195–9.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  129. Millward M, Price T, Townsend A, et al. Phase 1 clinical trial of the novel proteasome inhibitor marizomib with the histone deacetylase inhibitor vorinostat in patients with melanoma, pancreatic and lung cancer based on in vitro assessments of the combination. Invest New Drugs. 2012;30(6):2303–17.

    Article  CAS  PubMed  Google Scholar 

  130. Takeshima H, Wakabayashi M, Hattori N, et al. Identification of coexistence of DNA methylation and H3K27me3 specifically in cancer cells as a promising target for epigenetic therapy. Carcinogenesis. 2015;36(2):192–201.

    Article  PubMed  Google Scholar 

  131. Tanaka M, Roberts JM, Qi J, Bradner JE. Inhibitors of emerging epigenetic targets for cancer therapy: a patent review (2010–2014). Pharm Pat Anal. 2015;4(4):261–84.

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Laboratory of Cellular and Molecular Engineering “S. Cavalcanti”, Department of Electrical, Electronic and Information Engineering “G. Marconi” (DEI), University of Bologna, via Venezia 52, 47521, Cesena, FC, Italy

    Alice Pasini & Emanuele Giordano

  2. Department of Medical Oncology, IRCCS Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST), Meldola, FC, Italy

    Angelo Delmonte

  3. Biosciences Laboratory, IRCCS Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST), Meldola, FC, Italy

    Anna Tesei & Daniele Calistri

  4. Health Sciences and Technologies, Interdepartmental Center for Industrial Research (HST-ICIR), University of Bologna, Cesena, FC, Italy

    Emanuele Giordano

Authors
  1. Alice Pasini
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Angelo Delmonte
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Anna Tesei
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Daniele Calistri
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Emanuele Giordano
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Alice Pasini.

Ethics declarations

Funding

Charitable funding from Ni MA. s.r.l and S.G.M. Distribuzione s.r.l. is gratefully acknowledged.

Conflict of interest

Drs. Alice Pasini, Angelo Delmonte, Anna Tesei, Daniele Calistri and Emanuele Giordano declare no conflicts of interest or affiliations with any organization or entity with a direct financial interest in the subject matter or materials discussed in this paper.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Pasini, A., Delmonte, A., Tesei, A. et al. Targeting Chromatin-Mediated Transcriptional Control of Gene Expression in Non-Small Cell Lung Cancer Therapy: Preclinical Rationale and Clinical Results. Drugs 75, 1757–1771 (2015). https://doi.org/10.1007/s40265-015-0461-3

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s40265-015-0461-3

Keywords

Search

Navigation