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

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

Research output: Contribution to journalArticle

22 Citations (Scopus)

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 Fcã-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.

Original languageEnglish
Pages (from-to)2115-2122
Number of pages8
JournalOncology Reports
Volume31
Issue number5
DOIs
Publication statusPublished - 2014

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Antibody-Dependent Cell Cytotoxicity
Epidermal Growth Factor Receptor
Colorectal Neoplasms
Tumor Cell Line
Blood Cells
Cetuximab
Cell Line
Neoplasms
Epidermal Growth Factor
Natural Killer Cells
Immunoglobulin G
Immunohistochemistry
Monoclonal Antibodies
Tissue Donors

Keywords

  • Antibody-dependent cell-mediated cytotoxicity
  • Cell surface expression
  • Cetuximab
  • Colorectal cancer
  • Epidermal growth factor receptor

ASJC Scopus subject areas

  • Cancer Research
  • Oncology
  • Medicine(all)

Cite this

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, Yuukou.

In: Oncology Reports, Vol. 31, No. 5, 2014, p. 2115-2122.

Research output: Contribution to journalArticle

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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 Fc{\~a}-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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AU - Seo, Yuki

AU - Ishii, Yoshiyuki

AU - Ochiai, Hiroki

AU - Fukuda, Kazumasa

AU - Akimoto, Shingo

AU - Hayashida, Tetsu

AU - Okabayashi, Koji

AU - Tsuruta, Masashi

AU - Hasegawa, Hirotoshi

AU - Kitagawa, Yuukou

PY - 2014

Y1 - 2014

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