Cetuximab-mediated ADCC activity is correlated with the cell surface expression level of EGFR but not with the KRAS/BRAF mutational status in colorectal cancer

Seo,Yuki; Ishii,Yoshiyuki; Ochiai,Hiroki; Fukuda,Kazumasa; Akimoto,Shingo; Hayashida,Tetsu; Okabayashi,Koji; Tsuruta,Masashi; Hasegawa,Hirotoshi; Kitagawa,Yuko

doi:10.3892/or.2014.3077

May-2014 Volume 31 Issue 5

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May-2014 Volume 31 Issue 5

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Article

Cetuximab-mediated ADCC activity is correlated with the cell surface expression level of EGFR but not with the KRAS/BRAF mutational status in colorectal cancer

Authors:
- Yuki Seo
- Yoshiyuki Ishii
- Hiroki Ochiai
- Kazumasa Fukuda
- Shingo Akimoto
- Tetsu Hayashida
- Koji Okabayashi
- Masashi Tsuruta
- Hirotoshi Hasegawa
- Yuko Kitagawa
View Affiliations / Copyright

Affiliations: Department of Surgery, Keio University School of Medicine, Shinjuku-ku, Tokyo 160-8582, Japan
Pages: 2115-2122
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Published online on: March 11, 2014

https://doi.org/10.3892/or.2014.3077
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Abstract

Cetuximab, an IgG1 monoclonal antibody against the epidermal growth factor receptor (EGFR), is widely used for the treatment of metastatic colorectal cancer (mCRC). One of the mechanisms of action is considered to be antibody-dependent cell-mediated cytotoxicity (ADCC) triggered by Fcγ-R on natural killer cells. However, whether ADCC is associated with EGFR expression and/or the mutational status of EGF downstream effectors (KRAS and BRAF) in colorectal cancer (CRC) remains unclear. The aim of the present study was to verify whether ADCC activities are associated with the cell surface expression levels of EGFR and/or the mutational status of KRAS and BRAF. Five human CRC cell lines with different cell surface expression levels of EGFR and different KRAS and BRAF mutational statuses were selected to evaluate ADCC activity using peripheral blood mononuclear cells (PBMCs) from healthy human donors. Furthermore, tumor cells from resected specimens of CRC patients were used to evaluate the cell surface expression level of EGFR using immunohistochemistry and the KRAS and BRAF mutational statuses using direct sequencing, while the ADCC activity was examined using PBMCs from the same CRC patients. A strong correlation was observed between the expression levels of EGFR and the ADCC activities in the cell lines (correlation coefficient: 0.949; P=0.003). Of the 13 resected specimens, a high ADCC activity level was significantly observed in tumor cells with high expression levels of cell surface EGFR, when compared with that in the tumor cells with low expression levels (P=0.027). In both CRC cell lines and tumor cells from CRC patients, the ADCC activities were significantly associated with the cell surface expression levels of EGFR [standard partial regression coefficients: 0.911 (P=0.017) and 0.660 (P=0.018), respectively], but not with the mutational status of KRAS and BRAF [standard partial regression coefficient: -0.101 (P=0.631) and 0.160 (P=0.510), respectively]. Cetuximab-mediated ADCC activity may be correlated with the cell surface expression level of EGFR, regardless of the mutational statuses of KRAS and BRAF, in CRC.

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1	Kopetz S, Chang GJ, Overman MJ, et al: Improved survival in metastatic colorectal cancer is associated with adoption of hepatic resection and improved chemotherapy. J Clin Oncol. 27:3677–3683. 2009. View Article : Google Scholar : PubMed/NCBI
2	Marechal R, De Schutter J, Nagy N, et al: Putative contribution of CD56 positive cells in cetuximab treatment efficacy in first-line metastatic colorectal cancer patients. BMC Cancer. 10:340–350. 2010. View Article : Google Scholar : PubMed/NCBI
3	Tejpar S, Celik I, Schlichting M, Sartorius U, Bokemeyer C and Van Cutsem E: Association of KRAS G13D tumor mutations with outcome in patients with metastatic colorectal cancer treated with first-line chemotherapy with or without cetuximab. J Clin Oncol. 30:3570–3577. 2012.PubMed/NCBI
4	Correale P, Marra M, Remondo C, et al: Cytotoxic drugs up-regulate epidermal growth factor receptor (EGFR) expression in colon cancer cells and enhance their susceptibility to EGFR-targeted antibody-dependent cell-mediated-cytotoxicity (ADCC). Eur J Cancer. 46:1703–1711. 2010. View Article : Google Scholar
5	Xu H, Yu Y, Marciniak D, Rishi AK, Sarkar FH, Kucuk O and Majumdar AP: Epidermal growth factor receptor (EGFR)-related protein inhibits multiple members of the EGFR family in colon and breast cancer cells. Mol Cancer Ther. 4:435–442. 2005.PubMed/NCBI
6	Yang JL, Qu XJ, Russell PJ and Goldstein D: Regulation of epidermal growth factor receptor in human colon cancer cell lines by interferon α. Gut. 53:123–129. 2004.
7	Buck E, Eyzaguirre A, Barr S, et al: Loss of homotypic cell adhesion by epithelial-mesenchymal transition or mutation limits sensitivity to epidermal growth factor receptor inhibition. Mol Cancer Ther. 6:532–541. 2007. View Article : Google Scholar : PubMed/NCBI
8	Ikehara N, Semba S, Sakashita M, Aoyama N, Kasuga M and Yokozaki H: BRAF mutation associated with dysregulation of apoptosis in human colorectal neoplasms. Int J Cancer. 115:943–950. 2005. View Article : Google Scholar : PubMed/NCBI
9	Koizumi F, Kanzawa F, Ueda Y, et al: Synergistic interaction between the EGFR tyrosine kinase inhibitor gefitinib (‘Iressa’) and the DNA topoisomerase I inhibitor CPT-11 (irinotecan) in human colorectal cancer cells. Int J Cancer. 108:464–472. 2004.
10	Balin-Gauthier D, Delord JP, Rochaix P, et al: In vivo and in vitro antitumor activity of oxaliplatin in combination with cetuximab in human colorectal tumor cell lines expressing different level of EGFR. Cancer Chemother Pharmacol. 57:709–718. 2006. View Article : Google Scholar
11	Shigeta K, Hayashida T, Hoshino Y, et al: Expression of epidermal growth factor receptor detected by cetuximab indicates its efficacy to inhibit in vitro and in vivo proliferation of colorectal cancer cells. PLoS One. 8:e663022013. View Article : Google Scholar : PubMed/NCBI
12	Wolff A, Hammond M, Schwartz J, et al: American Society of Clinical Oncology/College of American Pathologists guideline recommendations for human epidermal growth factor receptor 2 testing in breast cancer. J Clin Oncol. 25:118–145. 2007. View Article : Google Scholar
13	De Roock W, Piessevaux H, De Schutter J, et al: KRAS wild-type state predicts survival and is associated to early radiological response in metastatic colorectal cancer treated with cetuximab. Ann Oncol. 19:508–515. 2008.PubMed/NCBI
14	Steplewski Z, Sun LK, Shearman CW, Ghrayeb J, Daddona P and Koprowski H: Biological activity of human-mouse IgG1, IgG2, IgG3, and IgG4 chimeric monoclonal antibodies with antitumor specificity. Proc Natl Acad Sci USA. 85:4852–4856. 1988. View Article : Google Scholar : PubMed/NCBI
15	Montagut C, Dalmases A, Bellosillo B, et al: Identification of a mutation in the extracellular domain of the Epidermal Growth Factor Receptor conferring cetuximab resistance in colorectal cancer. Nat Med. 18:221–223. 2012. View Article : Google Scholar : PubMed/NCBI
16	Luo FR, Yang Z, Dong H, et al: Correlation of pharmacokinetics with the antitumor activity of Cetuximab in nude mice bearing the GEO human colon carcinoma xenograft. Cancer Chemother Pharmacol. 56:455–464. 2005. View Article : Google Scholar : PubMed/NCBI
17	Kurai J, Chikumi H, Hashimoto K, et al: 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	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 : PubMed/NCBI

Journals

International Journal of Molecular Medicine

International Journal of Oncology

Molecular Medicine Reports

Oncology Reports

Experimental and Therapeutic Medicine

Oncology Letters

Biomedical Reports

Molecular and Clinical Oncology

World Academy of Sciences Journal

International Journal of Functional Nutrition

International Journal of Epigenetics

Medicine International

Cetuximab-mediated ADCC activity is correlated with the cell surface expression level of EGFR but not with the KRAS/BRAF mutational status in colorectal cancer

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