Cetuximab promotes anticancer drug toxicity in rhabdomyosarcomas with EGFR amplification in vitro

  • Authors:
    • Yuki Yamamoto
    • Kazumasa Fukuda
    • Yasushi Fuchimoto
    • Yumi Matsuzaki
    • Yoshiro Saikawa
    • Yuko Kitagawa
    • Yasuhide Morikawa
    • Tatsuo Kuroda
  • View Affiliations

  • Published online on: July 4, 2013     https://doi.org/10.3892/or.2013.2588
  • Pages: 1081-1086
Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )
Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )


Abstract

Overexpression of human epidermal growth factor receptor (EGFR) has been detected in various tumors and is associated with poor outcomes. Combination treatment regimens with EGFR-targeting and cytotoxic agents are a potential therapeutic option for rhabdomyosarcoma (RMS) with EGFR amplification. We investigated the effects of combination treatment with actinomycin D and the EGFR-targeting agent cetuximab in 4 RMS cell lines. All 4 RMS cell lines expressed wild-type K-ras, and 2 of the 4 overexpressed EGFR, as determined by flow cytometry, real-time PCR and direct sequencing. Combination of cetuximab and actinomycin D was highly effective, synergistically inhibiting cell growth with a combination index of less than 1. Moreover, combination treatment with these two reagents increased the rate of apoptosis in EGFR-positive cells. Cetuximab has antitumor activity in EGFR-amplified RMS cells when combined with antitumor reagents, indicating that cetuximab is a potential therapeutic reagent for RMS with EGFR amplification.

References

1 

McDowell HP: Update on childhood rhabdomyosarcoma. Arch Dis Child. 88:354–357. 2003. View Article : Google Scholar

2 

Pappo AS, Shapiro DN, Crist WM and Maurer HM: Biology and therapy of pediatric rhabdomyosarcoma. J Clin Oncol. 13:2123–2139. 1995.PubMed/NCBI

3 

Wolden SL, Anderson JR, Crist WM, Breneman JC, Wharam MD Jr, Wiener ES, Qualman SJ and Donaldson SS: Indications for radiotherapy and chemotherapy after complete resection in rhabdomyosarcoma: a report from the Intergroup Rhabdomyosarcoma Studies I to III. J Clin Oncol. 17:3468–3475. 1999.PubMed/NCBI

4 

Koscielniak E, Morgan M and Treuner J: Soft tissue sarcoma in children: prognosis and management. Paediatr Drugs. 4:21–28. 2002. View Article : Google Scholar : PubMed/NCBI

5 

Ma WW and Adjei AA: Novel agents on the horizon for cancer therapy. CA Cancer J Clin. 59:111–137. 2009. View Article : Google Scholar : PubMed/NCBI

6 

Capdevila J, Elez E, Macarulla T, Ramos FJ, Ruiz-Echarri M and Tabernero J: Anti-epidermal growth factor receptor monoclonal antibodies in cancer treatment. Cancer Treat Rev. 35:354–363. 2009. View Article : Google Scholar : PubMed/NCBI

7 

Cunningham D, Humblet Y, Siena S, Khayat D, Bleiberg H, Santoro A, Bets D, Mueser M, Harstrick A, Verslype C, Chau I and Van Cutsem E: Cetuximab monotherapy and cetuximab plus irinotecan in irinotecan-refractory metastatic colorectal cancer. N Engl J Med. 351:337–345. 2004. View Article : Google Scholar : PubMed/NCBI

8 

Herbst RS, Arquette M, Shin DM, Dicke K, Vokes EE, Azarnia N, Hong WK and Kies MS: Phase II multicenter study of the epidermal growth factor receptor antibody cetuximab and cisplatin for recurrent and refractory squamous cell carcinoma of the head and neck. J Clin Oncol. 23:5578–5587. 2005. View Article : Google Scholar : PubMed/NCBI

9 

Vermorken JB: Squamous cell carcinoma of the head and neck. J BUON. 7:311–317. 2002.PubMed/NCBI

10 

Peng D, Fan Z, Lu Y, DeBlasio T, Scher H and Mendelsohn J: Anti-epidermal growth factor receptor monoclonal antibody 225 up-regulates p27KIP1 and induces G1 arrest in prostatic cancer cell line DU145. Cancer Res. 56:3666–3669. 1996.PubMed/NCBI

11 

Wu X, Fan Z, Masui H, Rosen N and Mendelsohn J: Apoptosis induced by an anti-epidermal growth factor receptor monoclonal antibody in a human colorectal carcinoma cell line and its delay by insulin. J Clin Invest. 95:1897–1905. 1995. View Article : Google Scholar : PubMed/NCBI

12 

Perrotte P, Matsumoto T, Inoue K, Kuniyasu K, Eve BY, Hicklin DJ, Radinsky R and Dinney CPN: Anti-epidermal growth factor receptor antibody C225 inhibits angiogenesis in human transitional cell carcinoma growing orthotopically in nude mice. Clin Cancer Res. 5:257–265. 1999.PubMed/NCBI

13 

Liu B, Fang M, Lu Y, Mendelsohn J and Fan Z: Fibroblast growth factor and insulin-like growth factor differentially modulate the apoptosis and G1 arrest induced by anti-epidermal growth factor receptor monoclonal antibody. Oncogene. 20:1913–1922. 2001. View Article : Google Scholar

14 

Ciardiello F, Bianco R, Damiano V, De Lorenzo S, Pepe S, De Placido S, Fan Z, Mendelsohn J, Bianco AR and Tortora G: Antitumor activity of sequential treatment with topotecan and anti-epidermal growth factor receptor monoclonal antibody C225. Clin Cancer Res. 5:909–916. 1999.PubMed/NCBI

15 

Kawaguchi Y, Kono K, Mimura K, Sugai H, Akaike H and Fujii H: Cetuximab induce antibody-dependent cellular cytotoxicity against EGFR-expressing esophageal squamous cell carcinoma. Int J Cancer. 120:781–787. 2007. View Article : Google Scholar

16 

Kimura H, Sakai K, Arao T, Shimoyama T, Tamura T and Nishio K: Antibody-dependent cellular cytotoxicity of cetuximab against tumor cells with wild-type or mutant epidermal growth factor receptor. Cancer Sci. 98:1275–1280. 2007. View Article : Google Scholar

17 

Kurai J, Chikumi H, Hashimoto K, Yamaguchi K, Yamasaki A, Sako T, Touge H, Makino H, Takata M, Miyata M, Nakamoto M, Burioka N and Shimizu E: Antibody-dependent cellular cytotoxicity mediated by cetuximab against lung cancer cell lines. Clin Cancer Res. 13:1552–1561. 2007. View Article : Google Scholar : PubMed/NCBI

18 

Naramura M, Gillies SD, Mendelsohn J, Reisfeld RA and Mueller BM: Therapeutic potential of chimeric and murine anti-(epidermal growth factor receptor) antibodies in a metastasis model for human melanoma. Cancer Immunol Immunother. 37:343–349. 1993. View Article : Google Scholar : PubMed/NCBI

19 

Chou TC and Talalay P: Quantitative analysis of dose-effect relationships: the combined effects of multiple drugs or enzyme inhibitors. Adv Enzyme Regul. 22:27–55. 1984. View Article : Google Scholar : PubMed/NCBI

20 

Livak KJ and Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) method. Methods. 25:402–408. 2001. View Article : Google Scholar : PubMed/NCBI

21 

Sato O, Wada T, Kawai A, Yamaguchi U, Makimoto A, Kokai Y, Yamashita T, Chuman H, Beppu Y, Tani Y and Hasegawa T: Expression of epidermal growth factor receptor, ERBB2 and KIT in adult soft tissue sarcomas: a clinicopathologic study of 281 cases. Cancer. 103:1881–1890. 2005. View Article : Google Scholar : PubMed/NCBI

22 

Ganti R, Skapek SX, Zhang J, Fuller CE, Wu J, Billups CA, Breitfeld PP, Dalton JD, Meyer WH and Khoury JD: Expression and genomic status of EGFR and ErbB-2 in alveolar and embryonal rhabdomyosarcoma. Mod Pathol. 19:1213–1220. 2006. View Article : Google Scholar : PubMed/NCBI

23 

Margue CM, Bernasconi M, Barr FG and Schäfer BW: Transcriptional modulation of the anti-apoptotic protein BCL-XL by the paired box transcription factors PAX3 and PAX3/FKHR. Oncogene. 19:2921–2929. 2000. View Article : Google Scholar : PubMed/NCBI

24 

Laé M, Ahn EH, Mercado GE, Chuai S, Edgar M, Pawel BR, Olshen A, Barr FG and Ladanyi M: Global gene expression profiling of PAX-FKHR fusion-positive alveolar and PAX-FKHR fusion-negative embryonal rhabdomyosarcomas. J Pathol. 212:143–151. 2007.PubMed/NCBI

25 

Tomescu O, Xia SJ, Strezlecki D, Bennicelli JL, Ginsberg J, Pawel B and Barr FG: Inducible short-term and stable long-term cell culture systems reveal that the PAX3-FKHR fusion oncoprotein regulates CXCR4, PAX3, and PAX7 expression. Lab Invest. 84:1060–1070. 2004. View Article : Google Scholar : PubMed/NCBI

26 

Taulli R, Scuoppo C, Bersani F, Accornero P, Forni PE, Miretti S, Grinza A, Allegra P, Schmitt-Ney M, Crepaldi T and Ponzetto C: Validation of Met as a therapeutic target in alveolar and embryonal rhabdomyosarcoma. Cancer Res. 66:4742–4749. 2006. View Article : Google Scholar : PubMed/NCBI

27 

Mercado GE, Xia SJ, Zhang C, Ahn EH, Gustafson DM, Laé M, Ladanyi M and Barr FG: Identification of PAX3-FKHR-regulated genes differentially expressed between alveolar and embryonal rhabdomyosarcoma: focus on MYCN as a biologically relevant target. Genes Chromosomes Cancer. 47:510–520. 2008. View Article : Google Scholar

28 

Williamson D, Lu YJ, Gordon T, Sciot R, Kelsey A, Fisher C, Poremba C, Anderson J, Pritchard-Jones K and Shipley J: Relationship between MYCN copy number and expression in rhabdomyosarcomas and correlation with adverse prognosis in the alveolar subtype. J Clin Oncol. 23:880–888. 2005. View Article : Google Scholar : PubMed/NCBI

29 

Taniguchi E, Nishijo K, McCleish AT, Michalek JE, Grayson MH, Infante AJ, Abboud HE, Legallo RD, Qualman SJ, Rubin BP and Keller C: PDGFR-A is a therapeutic target in alveolar rhabdomyosarcoma. Oncogene. 27:6550–6560. 2008. View Article : Google Scholar : PubMed/NCBI

30 

Davicioni E, Anderson MJ, Finckenstein FG, Lynch JC, Qualman SJ, Shimada H, Schofield DE, Buckley JD, Meyer WH, Sorensen PHB and Triche TJ: Molecular classification of rhabdomyosarcoma - genotypic and phenotypic determinants of diagnosis: a report from the Children’s Oncology Group. Am J Pathol. 174:550–564. 2009.PubMed/NCBI

31 

Ebauer M, Wachtel M, Niggli FK and Schäfer BW: Comparative expression profiling identifies an in vivo target gene signature with TFAP2B as a mediator of the survival function of PAX3/FKHR. Oncogene. 26:7267–7281. 2007. View Article : Google Scholar : PubMed/NCBI

32 

Oda Y, Kohashi K, Yamamoto H, Tamiya S, Kohno K, Kuwano M, Iwamoto Y, Tajiri T, Taguchi T and Tsuneyoshi M: Different expression profiles of Y-box-binding protein-1 and multidrug resistance-associated proteins between alveolar and embryonal rhabdomyosarcoma. Cancer Sci. 99:726–732. 2008. View Article : Google Scholar

33 

Herrmann D, Seitz G, Warmann SW, Bonin M, Fuchs J and Armeanu-Ebinger S: Cetuximab promotes immunotoxicity against rhabdomyosarcoma in vitro. J Immunother. 33:279–286. 2010. View Article : Google Scholar : PubMed/NCBI

34 

Lièvre A, Bachet J-B, Le Corre D, Boige V, Landi B, Emile JF, Côté JF, Tomasic G, Penna C, Ducreux M, Rougier P, Penault-Llorca F and Laurent-Puig P: KRAS mutation status is predictive of response to cetuximab therapy in colorectal cancer. Cancer Res. 66:3992–3995. 2006.PubMed/NCBI

35 

Wellcome Trust Sanger Institute. Catalogue of Somatic Mutations in Cancer. http://www.sanger.ac.uk/genetics/CGP/cosmic/urisimplehttp://www.sanger.ac.uk/genetics/CGP/cosmic/. Accessed June 4, 2012

36 

Chen Y, Takita J, Hiwatari M, Igarashi T, Hanada R, Kikuchi A, Hongo T, Taki T, Ogasawara M, Shimada A and Hayashi Y: Mutations of the PTPN11 and RAS genes in rhabdomyosarcoma and pediatric hematological malignancies. Genes Chromosomes Cancer. 45:583–591. 2006. View Article : Google Scholar : PubMed/NCBI

37 

Bancroft CC, Chen Z, Yeh J, Sunwoo JB, Yeh NT, Jackson S, Jackson C and Van Waes C: Effects of pharmacologic antagonists of epidermal growth factor receptor, PI3K and MEK signal kinases on NF-kappaB and AP-1 activation and IL-8 and VEGF expression in human head and neck squamous cell carcinoma lines. Int J Cancer. 99:538–548. 2002. View Article : Google Scholar : PubMed/NCBI

38 

Raymond E, Faivre S and Armand JP: Epidermal growth factor receptor tyrosine kinase as a target for anticancer therapy. Drugs. 60(Suppl 1): 15–23. 2000. View Article : Google Scholar : PubMed/NCBI

Related Articles

Journal Cover

September 2013
Volume 30 Issue 3

Print ISSN: 1021-335X
Online ISSN:1791-2431

Sign up for eToc alerts

Recommend to Library

Copy and paste a formatted citation
APA
Yamamoto, Y., Fukuda, K., Fuchimoto, Y., Matsuzaki, Y., Saikawa, Y., Kitagawa, Y. ... Kuroda, T. (2013). Cetuximab promotes anticancer drug toxicity in rhabdomyosarcomas with EGFR amplification in vitro. Oncology Reports, 30, 1081-1086. https://doi.org/10.3892/or.2013.2588
MLA
Yamamoto, Y., Fukuda, K., Fuchimoto, Y., Matsuzaki, Y., Saikawa, Y., Kitagawa, Y., Morikawa, Y., Kuroda, T."Cetuximab promotes anticancer drug toxicity in rhabdomyosarcomas with EGFR amplification in vitro". Oncology Reports 30.3 (2013): 1081-1086.
Chicago
Yamamoto, Y., Fukuda, K., Fuchimoto, Y., Matsuzaki, Y., Saikawa, Y., Kitagawa, Y., Morikawa, Y., Kuroda, T."Cetuximab promotes anticancer drug toxicity in rhabdomyosarcomas with EGFR amplification in vitro". Oncology Reports 30, no. 3 (2013): 1081-1086. https://doi.org/10.3892/or.2013.2588