The anti-EGFR monoclonal antibody blocks cisplatin-induced activation of EGFR signaling mediated by HB-EGF.
Cisplatin is a key agent in combination chemotherapy for various types of solid tumor. We now show that cisplatin activates signaling by the epidermal growth factor receptor (EGFR) by inducing cleavage of heparin-binding epidermal growth factor-like growth factor (HB-EGF). Matuzumab, a monoclonal antibody to EGFR, inhibited cisplatin-induced EGFR signaling, likely through competition with the soluble form of HB-EGF for binding to EGFR. Matuzumab enhanced the antitumor effect of cisplatin in nude mice harboring human non-small cell lung cancer xenografts. Our findings shed light on the mechanism by which monoclonal antibodies to EGFR might augment the efficacy of cisplatin.
Yoshida
Takeshi
T
Department of Medical Oncology, Kinki University School of Medicine, 377-2 Ohno-higashi, Osaka-Sayama, Osaka 589-8511, Japan.
Okamoto
Isamu
I
Iwasa
Tsutomu
T
Fukuoka
Masahiro
M
Nakagawa
Kazuhiko
K
D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002945:Cisplatin / Q000494:pharmacology*; D066246:ErbB Receptors / Q000819:agonists / Q000037:antagonists & inhibitors* / Q000378:metabolism; D005260:Female; D066257:Heparin-binding EGF-like Growth Factor; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism; D008175:Lung Neoplasms / Q000378:metabolism*; D051379:Mice; D008819:Mice, Nude; D055752:Small Cell Lung Carcinoma / Q000378:metabolism*; D023041:Xenograft Model Antitumor Assays
D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; C587883:HBEGF protein, human; C587884:Hbegf protein, mouse; D066257:Heparin-binding EGF-like Growth Factor; D036341:Intercellular Signaling Peptides and Proteins; C512478:EGFR protein, human; D066246:ErbB Receptors; C520777:matuzumab; D002945:Cisplatin