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Open Access 01-12-2021 | Sarcoma | Research

Histone deacetylase inhibitor panobinostat induces antitumor activity in epithelioid sarcoma and rhabdoid tumor by growth factor receptor modulation

Authors: Anne Catherine Harttrampf, Maria Eugenia Marques da Costa, Aline Renoult, Estelle Daudigeos-Dubus, Birgit Geoerger

Published in: BMC Cancer | Issue 1/2021

Abstract

Background

Epithelioid sarcomas and rhabdoid tumors are rare, aggressive malignancies with poor prognosis. Both are characterized by INI1 alterations and deregulation of growth factor receptors albeit their interaction has not been elucidated.

Methods

In this study, we investigated the activity of a panel of epigenetic modulators and receptor tyrosine kinase inhibitors in vitro on respective cell lines as well as on primary patient-derived epithelioid sarcoma cells, and in vivo on xenografted mice. Focusing on histone deacetylase (HDAC) inhibitors, we studied the mechanism of action of this class of agents, its effect on growth factor receptor regulation, and changes in epithelial-to-mesenchymal transition by using cell- and RT-qPCR-based assays.

Results

Pan-HDAC inhibitor panobinostat exhibited potent anti-proliferative activity at low nanomolar concentrations in A204 rhabdoid tumor, and VAESBJ/GRU1 epithelioid sarcoma cell lines, strongly induced apoptosis, and resulted in significant tumor growth inhibition in VAESBJ xenografts. It differentially regulated EGFR, FGFR1 and FGFR2, leading to downregulation of EGFR in epithelioid sarcoma and to mesenchymal-to-epithelial transition whereas in rhabdoid tumor cells, EGFR was strongly upregulated and reinforced the mesenchymal phenotype. All three cell lines were rendered more susceptible towards combination with EGFF inhibitor erlotinib, further enhancing apoptosis.

Conclusions

HDAC inhibitors exhibit significant anticancer activity due to their multifaceted actions on cytotoxicity, differentiation and drug sensitization. Our data suggest that the tailored, tissue-specific combination of HDAC inhibitors with therapeutics which target cellular salvage mechanisms might increase their therapeutic relevance.

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Chbani L, Guillou L, Terrier P, Decouvelaere AV, Grégoire F, Terrier-Lacombe MJ, et al. Epithelioid sarcoma a clinicopathologic and immunohistochemical analysis of 106 cases from the french sarcoma group. Am J Clin Pathol. 2009;131(2):222–7. https://doi.org/10.1309/AJCPU98ABIPVJAIV.CrossRefPubMed

Manivel JC, Wick MR, SR DLP. Epithelioid sarcoma. An immunohistochemical study. Am J Clin Pathol. 1987;87(3):319–26.CrossRef

Jawad MU, Extein J, Min ES, Scully SP. Prognostic factors for survival in patients with epithelioid sarcoma: 441 cases from the SEER database. Clin Orthop Relat Res. 2009;467(11):2939–48. https://doi.org/10.1007/s11999-009-0749-2.CrossRefPubMedPubMedCentral

Armah HB, Parwani AV. Epithelioid sarcoma. Arch Pathol Lab Med. 2009;133(5):814–9. https://doi.org/10.5858/133.5.814.CrossRefPubMed

Nemes K, Frühwald MC. Emerging therapeutic targets for the treatment of malignant rhabdoid tumors. Expert Opin Ther Targets. 2018;22(4):365–79. https://doi.org/10.1080/14728222.2018.1451839.CrossRefPubMed

Sullivan LM, Folpe AL, Pawel BR, Judkins AR, Biegel J. a. Epithelioid sarcoma is associated with a high percentage of SMARCB1 deletions. Mod Pathol. 2012;26(3):385–92. https://doi.org/10.1038/modpathol.2012.175.CrossRefPubMedPubMedCentral

Versteege I, Sévenet N, Lange J, Rousseau-Merck MF, Ambros P, Handgretinger R, et al. Truncating mutations of hSNF5/INI1 in aggressive paediatric cancer. Nature. 1998;394(6689):203–6. https://doi.org/10.1038/28212.CrossRefPubMed

Roberts CW, Galusha SA, McMenamin ME, Fletcher CD, Orkin SH. Haploinsufficiency of Snf5 (integrase interactor 1) predisposes to malignant rhabdoid tumors in mice. Proc Natl Acad Sci U S A. 2000;97(25):13796–800. https://doi.org/10.1073/pnas.250492697.CrossRefPubMedPubMedCentral

Klochendler-Yeivin A, Fiette L, Barra J, Muchardt C, Babinet C, Yaniv M. The murine SNF5/INI1 chromatin remodeling factor is essential for embryonic development and tumor suppression. EMBO Rep. 2000;1(6):500–6. https://doi.org/10.1093/embo-reports/kvd129.CrossRefPubMedPubMedCentral

10.

Lopez G, Song Y, Lam R, Ruder D, Creighton CJ, Bid HK, et al. HDAC inhibition for the treatment of Epithelioid sarcoma: novel cross talk between epigenetic components. Mol Cancer Res. 2016;14(1):35–43. https://doi.org/10.1158/1541-7786.MCR-15-0295.CrossRefPubMed

11.

Moreno N, Kerl K. Preclinical evaluation of combined targeted approaches in malignant Rhabdoid tumors. Anticancer Res. 2016;3888(36):3883–7.

12.

Unland R, Borchardt C, Clemens D, Kool M, Dirksen U, Frühwald MC. Analysis of the antiproliferative effects of 3-deazaneoplanocin a in combination with standard anticancer agents in rhabdoid tumor cell lines. Anti-Cancer Drugs. 2015;26(3):301–11. https://doi.org/10.1097/CAD.0000000000000181.CrossRefPubMed

13.

Li Y, Seto E. HDACs and HDAC Inhibitors in Cancer Development and Therapy. Cold Spring Harbor Perspect Med. 2017;6(10). https://doi.org/10.1101/cshperspect.a026831.

14.

Algar EM, Muscat A, Dagar V, Rickert C, Chow CW, Jaclyn A, et al. Imprinted CDKN1C is a tumor suppressor in Rhabdoid tumor and activated by restoration of SMARCB1 and histone Deacetylase inhibitors. PLoS One. 2009;4(2):e4482. https://doi.org/10.1371/journal.pone.0004482.CrossRefPubMedPubMedCentral

15.

Muscat A, Popovski D, Jayasekara WSN, Rossello FJ, Ferguson M, Marini KD, et al. Low-dose histone Deacetylase inhibitor treatment leads to tumor growth arrest and multi-lineage differentiation of malignant Rhabdoid tumors. Clin Cancer Res. 2016;22(14):3560–71. https://doi.org/10.1158/1078-0432.CCR-15-2260.CrossRefPubMed

16.

Nieto MA, Huang RYYJ, Jackson RA, Thiery JPP. EMT: 2016. Cell. 2016;166(1):21–45. https://doi.org/10.1016/j.cell.2016.06.028.CrossRef

17.

Tam WL, Weinberg RA. The epigenetics of epithelial-mesenchymal plasticity in cancer. Nat Med. 2013;19(11):1438–49. https://doi.org/10.1038/nm.3336.CrossRefPubMedPubMedCentral

18.

Ren S, Su C, Wang Z, Li J, Fan L, Li B, et al. Epithelial phenotype as a predictive marker for response to. Int J Cancer. 2014;135(12):2962–71. https://doi.org/10.1002/ijc.28925.CrossRefPubMed

19.

Darr J, Klochendler A, Isaac S, Geiger T, Eden A. Phosphoproteomic analysis reveals Smarcb1 dependent EGFR signaling in malignant Rhabdoid tumor cells. Mol Cancer. 2015;14(1):167. https://doi.org/10.1186/s12943-015-0439-5.CrossRefPubMedPubMedCentral

20.

Wong JP, Todd JR, Finetti MA, Natrajan RC, Williamson D, Huang PH, et al. Dual targeting of PDGFR a and FGFR1 displays synergistic efficacy in malignant Rhabdoid tumors report dual targeting of PDGFR a and FGFR1 displays synergistic efficacy in malignant Rhabdoid tumors. Cell Rep. 2016;17(5):1265–75. https://doi.org/10.1016/j.celrep.2016.10.005.CrossRefPubMedPubMedCentral

21.

Chauvin C, Leruste A, Tauziede-Espariat A, Andrianteranagna M, Surdez D, Lescure A, et al. High-throughput drug screening identifies Pazopanib and Clofilium Tosylate as promising treatments for malignant Rhabdoid tumors report high-throughput drug screening identifies Pazopanib and Clofilium Tosylate as promising treatments for malignant Rhabdo. Cell Rep. 2017;21(7):1737–45. https://doi.org/10.1016/j.celrep.2017.10.076.CrossRefPubMed

22.

Wöhrle S, Weiss A, Ito M, Kauffmann A, Murakami M, Jagani Z, et al. Fibroblast growth factor receptors as novel therapeutic targets in SNF5-deleted malignant rhabdoid tumors. PLoS One. 2013;8(10):e77652. https://doi.org/10.1371/journal.pone.0077652.CrossRefPubMedPubMedCentral

23.

Cascio MJ, O’Donnell RJ, Horvai AE. Epithelioid sarcoma expresses epidermal growth factor receptor but gene amplification and kinase domain mutations are rare. Mod Pathol. 2010;23(4):574–80. https://doi.org/10.1038/modpathol.2010.2.CrossRefPubMed

24.

Xie X, Ghadimi MPH, Young ED, Belousov R, Zhu QS, Liu J, et al. Combining EGFR and mTOR blockade for the treatment of epithelioid sarcoma. Clin Cancer Res. 2011;17(18):5901–12. https://doi.org/10.1158/1078-0432.CCR-11-0660.CrossRefPubMedPubMedCentral

25.

Evrot E, Ebel N, Romanet V, Roelli C, Andraos R, Qian Z, et al. JAK1/2 and pan-deacetylase inhibitor combination therapy yields improved efficacy in preclinical mouse models of JAK2V617F-driven disease. Clin Cancer Res. 2013;19(22):6230–41. https://doi.org/10.1158/1078-0432.CCR-13-0905.CrossRefPubMed

26.

Daudigeos-Dubus E, Le Dret L, Lanvers-Kaminsky C, Bawa O, Opolon P, Vievard A, et al. Regorafenib: antitumor activity upon mono and combination therapy in preclinical pediatric malignancy models. PLoS One. 2015;10(11):e0142612. https://doi.org/10.1371/journal.pone.0142612.CrossRefPubMedPubMedCentral

27.

Harttrampf AC, Lacroix L, Deloger M, Deschamps F, Puget S, Auger N, et al. Molecular screening for Cancer treatment optimization (MOSCATO-01) in pediatric patients: a single-institutional prospective molecular stratification trial. Clin Cancer Res. 2017;23(20):6101–12. https://doi.org/10.1158/1078-0432.CCR-17-0381.CrossRefPubMed

28.

You JS, Jones PA. Cancer genetics and epigenetics : two sides of the same coin? Cancer Cell. 2012;22(1):9–20. https://doi.org/10.1016/j.ccr.2012.06.008.CrossRefPubMedPubMedCentral

29.

Feinberg AP, Koldobskiy MA, Göndör A. Epigenetic modulators, modifiers and mediators in cancer aetiology and progression. Nat Rev Genet. 2016;17(5):284–99. https://doi.org/10.1038/nrg.2016.13.CrossRefPubMedPubMedCentral

30.

Kerl K, Ries D, Unland R, Borchert C, Moreno N, Hasselblatt M, et al. The histone deacetylase inhibitor SAHA acts in synergism with fenretinide and doxorubicin to control growth of rhabdoid tumor cells. BMC Cancer. 2013;13(1):286. https://doi.org/10.1186/1471-2407-13-286.CrossRefPubMedPubMedCentral

31.

Atadja P. Development of the pan-DAC inhibitor panobinostat (LBH589): successes and challenges. Cancer Lett. 2009;280(2):233–41. https://doi.org/10.1016/j.canlet.2009.02.019.CrossRefPubMed

32.

Kim KH, Roberts CWM. Mechanisms by which SMARCB1 loss drives rhabdoid tumor growth. Cancer Gene Ther. 2014;207(9):365–72. https://doi.org/10.1016/j.cancergen.2014.04.004.CrossRef

33.

Nicholson R, Gee J, Harper M. EGFR and cancer prognosis. Eur J Cancer. 2001;37(4):S9–15.CrossRef

34.

Chou CW, Wu MS, Huang WC, Chen CC. HDAC inhibition decreases the expression of EGFR in colorectal cancer cells. PLoS One. 2011;6(3):e18087. https://doi.org/10.1371/journal.pone.0018087.CrossRefPubMedPubMedCentral

35.

Edwards A, Li J, Atadja P, Bhalla K, Haura EB. Effect of the histone deacetylase inhibitor LBH589 against epidermal growth factor receptor-dependent human lung cancer cells. Mol Cancer Ther. 2007;6(9):2515–24. https://doi.org/10.1158/1535-7163.MCT-06-0761.CrossRefPubMed

36.

Lynch TJ, Bell DW, Sordella R, Gurubhagavatula S, Okimoto RA, Brannigan BW, et al. Activating mutations in the epidermal growth factor receptor underlying responsiveness of non–small-cell lung Cancer to Gefitinib. N Engl J Med. 2004;350(21):2129–39. https://doi.org/10.1056/NEJMoa040938.CrossRefPubMed

37.

Paez JG, Ja PA, Tracy S, Greulich H, Gabriel S, Herman P, et al. EGFR mutations in lung Cancer: correlation with clinical response to Gefitinib therapy. Science. 2004;304(5676):1497–501. https://doi.org/10.1126/science.1099314.CrossRefPubMed

38.

Ahsan A, Ramanand SG, Whitehead C, Hiniker SM, Rehemtulla A, Pratt WB, et al. Wild-type EGFR is stabilized by direct interaction with HSP90. Neoplasia. 2012;14(8):670–7. https://doi.org/10.1593/neo.12986.CrossRefPubMedPubMedCentral

39.

Kuwahara Y, Hosoi H, Osone S, Kita M, Iehara T, Kuroda H, et al. Antitumor activity of Gefitinib in malignant Rhabdoid tumor cells in vitro and in vivo. Clin Cancer Res. 2004;10(17):5940–8. https://doi.org/10.1158/1078-0432.CCR-04-0192.CrossRefPubMed

40.

Frezza AM, Jones RL, Lo VS, Asano N, Lucibello F, Ben-ami E, et al. Anthracycline, Gemcitabine, and Pazopanib in Epithelioid Sarcoma A Multi-institutional Case Series. JAMA Oncol. 2018. https://doi.org/10.1001/jamaoncol.2018.0219.

41.

Ranieri D, Rosato B, Nanni M, Magenta A, Belleudi F, Torrisi MR. Expression of the FGFR2 mesenchymal splicing variant in epithelial cells drives epithelial-mesenchymal transition. Oncotarget. 2015;7(5):5440–60.CrossRef

42.

Witta SE, Gemmill RM, Hirsch FR, Coldren CD, Hedman K, Ravdel L, et al. Restoring E-Cadherin expression increases sensitivity to epidermal growth factor receptor inhibitors in lung Cancer cell lines. Cancer Res. 2006;2:944–51.CrossRef

43.

Yu W, Lu W, Chen G, Cheng F, Su H, Chen Y, et al. Inhibition of histone deacetylases sensitizes cell lung cancer cells to erlotinib in vitro and in vivo. Br J Pharmacol. 2017;174(20):3608–22. https://doi.org/10.1111/bph.13961.CrossRefPubMedPubMedCentral

44.

Xu WS, Parmigiani RB, Marks PA. Histone deacetylase inhibitors: molecular mechanisms of action. Oncogene. 2007;26(37):5541–52. https://doi.org/10.1038/sj.onc.1210620.CrossRefPubMed

45.

Jiang G, Wang H, Zhang F, Zhang K, Liu Z, Fang R, et al. Histone deacetylase inhibitor induction of epithelial – mesenchymal transitions via up-regulation of Snail facilitates cancer progression. Biochim Biophys Acta. 2013;1833(3):663–71. https://doi.org/10.1016/j.bbamcr.2012.12.002.CrossRefPubMed

46.

47.

Liu W, Chen M, Wang M, Lee Y. Cisplatin-selected resistance is associated with increased motility and stem-like properties via activation of STAT3/Snail axis in atypical teratoid/rhabdoid tumor cells. Oncotarget. 2015;6(3):1750–68. https://doi.org/10.18632/oncotarget.2737.CrossRefPubMedPubMedCentral

48.

Johann PD, Erkek S, Zapatka M, Hasselblatt M, Pfister SM, Kool M. Atypical Teratoid/Rhabdoid tumors are comprised of three epigenetic subgroups with distinct article atypical Teratoid / Rhabdoid tumors are comprised of three epigenetic subgroups with distinct enhancer landscapes. Cancer Cell. 2016;29(3):379–93. https://doi.org/10.1016/j.ccell.2016.02.001.CrossRefPubMed

49.

Grasso CS, Tang Y, Truffaux N, Berlow NE, Liu L, Debily M, et al. Functionally-defined therapeutic targets in diffuse intrinsic Pontine Glioma. Nat Med. 2016;21(6):555–9.CrossRef

50.

Hennika T, Hu G, Olaciregui NG, Barton KL, Ehteda A, Chitranjan A, et al. Pre-clinical study of Panobinostat in Xenograft and genetically engineered murine diffuse intrinsic Pontine Glioma models. PLoS One. 2017;12(1):e0169485. https://doi.org/10.1371/journal.pone.0169485.CrossRefPubMedPubMedCentral

51.

Singleton WGB, Bienemann AS, Woolley M, Johnson D, Lewis O, Wyatt MJ, et al. The distribution, clearance, and brainstem toxicity of panobinostat administered by convection-enhanced delivery. J Neurosurg Pediatr. 2018;22(3):288–96. https://doi.org/10.3171/2018.2.PEDS17663.CrossRefPubMed

52.

Pfister SX, Ashworth A. Marked for death: targeting epigenetic changes in cancer. Nat Rev Drug Discov. 2017;16(4):241–63. https://doi.org/10.1038/nrd.2016.256.CrossRefPubMed

53.

Suraweera A, Byrne KJO, Richard DJ, Chen S, Richard DJ. Combination Therapy with Histone Deacetylase inhibitors (HDACi) for the Treatment of Cancer: Achieving the Full Therapeutic Potential of HDACi. Front Oncol. 2018;8. https://doi.org/10.3389/fonc.2018.00092.

Title: Histone deacetylase inhibitor panobinostat induces antitumor activity in epithelioid sarcoma and rhabdoid tumor by growth factor receptor modulation
Authors: Anne Catherine Harttrampf
Maria Eugenia Marques da Costa
Aline Renoult
Estelle Daudigeos-Dubus
Birgit Geoerger
Publication date: 01-12-2021
Publisher: BioMed Central
Keywords: Sarcoma
Erlotinib
Regorafenib
Published in: BMC Cancer / Issue 1/2021
Electronic ISSN: 1471-2407
DOI: https://doi.org/10.1186/s12885-021-08579-w

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