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

The expression of the activated mitogen-activated kinases/extracellular sig nal-regulated kinases (ERKs) ERK1 and ERK2 was characterized in 101 human h ead and neck squamous carcinoma specimens. Activated ERK1/2 were detected a t different levels in the majority of these tumors, as assayed by immunosta ining with an antibody specific for the dually phosphorylated and activated ERK1 and ERK2. ERK1/2 activation levels were higher in tumors with advance d 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 = 0.0 66; positive trend) correlated with activation of ERK1/2. In a multivariate analysis, both TGF-<alpha> (P < 0.0001) and HER2 (P = 0.045) were independ ently 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 rece ptor-dependent model cells (A431 and DiFi), a specific EGF receptor tyrosin e kinase inhibitor ("Iressa"; ZD1839) and a chimeric anti-EGF receptor anti body ("Cetuximab"; C225) inhibited ERK 1/2 activation at concentrations tha t inhibited autocrine cell proliferation. In patients on treatment with C22 5, the activation of ERK1/2 in skin, an EGF receptor-dependent tissue, was lower compared with control skin. Parallel changes were seen in keratinocyt e Ki67 proliferation indexes in skin from C225-treated patients. Taken toge ther, these studies provide support for a role of activation of ERK1/2 in h ead and neck squamous carcinoma and a correlation with EGF receptor/TGF-<al pha> expression. The inhibition of ERK1/2 activation in vitro and in vivo b y compounds targeting the EGF receptor points to the interest of ERK1/2 as potential surrogate markers of EGF-receptor signaling in clinical therapeut ic studies.