Activated extracellular signal-regulated kinases: association with epidermal growth factor receptor/transforming growth factor α expression in head and neck squamous carcinoma and inhibition by anti- epidermal growth factor receptor treatments

Nicholson, Robert Ian, Albanell, J, Codony-Servat, J, Rojo, F, Del Campo, J. M., Mendelsohn, J., Baselga, J., Sauleda, S., Anido, J., Raspall, G., Giralt, J. and Roselló, J. 2001. Activated extracellular signal-regulated kinases: association with epidermal growth factor receptor/transforming growth factor α expression in head and neck squamous carcinoma and inhibition by anti- epidermal growth factor receptor treatments. Cancer Research 61 (17) , pp. 6500-6510.

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Abstract

The expression of the activated mitogen-activated kinases/extracellular signal-regulated kinases (ERKs) ERK1 and ERK2 was characterized in 101 humanhead and neck squamous carcinoma specimens. Activated ERK1/2were detected at different levels in the majority of these tumors, as assayed by immunostaining with an antibody specific for the dually phosphorylated and activated ERK1 and ERK2. ERK1/2 activation levels were higher in tumors with advanced regional lymph node metastasis (P = 0.048) and in relapsed tumors (P = 0.021). The expression of epidermal growth factor (EGF) receptor (P = 0.037), transforming growth factor alpha (TGF-alpha; P < 0.001), and HER2 (P = 0.066; positive trend) correlated with activation of ERK1/2. In a multivariate analysis, both TGF-alpha (P < 0.0001) and HER2 (P = 0.045) were independently correlated with ERK1/2 activation. In turn, activation of ERK1/2 was associated with a higher Ki-67 proliferative index (P = 0.002). In EGF receptor-dependent model cells (A431 and DiFi), a specific EGF receptor tyrosine kinase inhibitor ("Iressa"; ZD1839) and a chimeric anti-EGF receptor antibody ("Cetuximab"; C225) inhibited ERK 1/2 activation at concentrations that inhibited autocrine cell proliferation. In patients on treatment with C225, the activation of ERK1/2 in skin, an EGF receptor-dependent tissue, was lower compared with control skin. Parallel changes were seen in keratinocyte Ki67 proliferation indexes in skin from C225-treated patients. Taken together, these studies provide support for a role of activation of ERK1/2 in head and neck squamous carcinoma and a correlation with EGF receptor/TGF-alpha expression. The inhibition of ERK1/2 activation in vitro and in vivo by compounds targeting the EGF receptor points to the interest of ERK1/2 as potential surrogate markers of EGF-receptor signaling in clinical therapeutic studies.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Pharmacy
Publisher:	American Association for Cancer Research
ISSN:	0008-5472
Last Modified:	19 Mar 2016 22:02
URI:	https://orca.cardiff.ac.uk/id/eprint/941

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