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 language | English |
|---|---|
| Pages (from-to) | 2115-2122 |
| Number of pages | 8 |
| Journal | Oncology Reports |
| Volume | 31 |
| Issue number | 5 |
| DOIs | |
| Publication status | Published - 2014 |
Fingerprint
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 journal › Article
}
TY - JOUR
T1 - 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
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
N2 - 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.
AB - 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.
KW - Antibody-dependent cell-mediated cytotoxicity
KW - Cell surface expression
KW - Cetuximab
KW - Colorectal cancer
KW - Epidermal growth factor receptor
UR - http://www.scopus.com/inward/record.url?scp=84898604815&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84898604815&partnerID=8YFLogxK
U2 - 10.3892/or.2014.3077
DO - 10.3892/or.2014.3077
M3 - Article
C2 - 24626880
AN - SCOPUS:84898604815
VL - 31
SP - 2115
EP - 2122
JO - Oncology Reports
JF - Oncology Reports
SN - 1021-335X
IS - 5
ER -