BACKGROUND: Cervical cancer (CC) annually kills 288 000 women worldwide. Unfortunately, responses to chemoradiation are partial and are of short duration. As anti-EGFR monoclonal antibodies sensitise tumours, we investigated cetuximab's toxicity plus chemoradiation on CC cells, which express different EGFR levels. METHODS: EGFR, HER2, AKT and MAPK expression and phosphorylation status were determined by western blotting. Cytotoxicity was assessed by MTT or clonogenic assays (CA) in cell lines treated with cetuximab alone or in combinations. RESULTS: Cetuximab with cisplatin and radiation achieved maximum cytotoxic effects for A431, Caski and C33A cells (high, intermediate and low EGFR expression, respectively) in CA. Cetuximab efficiently decreased MAPK and AKT phosphorylation in A431 cells but slightly less in Caski and C33A cells. To check whether further EGFR, HER2 or MAPK inhibition would improve cetuximab's cytotoxicity, we combined it with an EGFR tyrosine kinase inhibitor (TKI), trastuzumab or a MEK1/2 inhibitor (PD98059). In Caski, but not in C33A cells, cetuximab cooperated with the TKI, reducing cell survival and AKT and MAPK phosphorylation. However, cetuximab with trastuzumab or PD98059 reduced survival and MAPK phosphorylation of both cell lines. CONCLUSION: Our data suggest that cetuximab combined with chemoradiation, trastuzumab or MAPK inhibitors has useful applications for CC treatment, independently of EGFR expression. Cervical cancer (CC) is a common malignancy which kills 288 000 women annually. Radical hysterectomy and radiation therapy are standard treatments for early-stage invasive CC, whereas pelvic radiation has been used for locally advanced cancers. Recently, an improved survival of patients with locally advanced CC was reported when platinum-based chemotherapy was combined with radiation treatment (Ota et al, 2007). However, despite technological advances, up to 35% of all CC patients will develop persistent/ recurrent/metastatic disease (Bellone et al, 2007).Infection of human keratinocytes by oncogenic HPV subtypes is critical for cervical carcinogenesis, however, it is not sufficient for cancer development. Among other molecular cofactors investigated, epidermal growth factor (EGF) receptor (EGFR) overexpression is frequent in CC and is an independent predictor of poor prognosis in advanced stage tumours (Kersemaekers et al, 1999). Epidermal growth factor receptor, a 170-kDa transmembrane glycoprotein, belongs to the ErbB/HER family of receptors, which include HER2 (ErbB2), HER3 (ErbB3) and HER4 (ErbB4). Ligand binding leads to the formation of homo-or heterodimers with other members of the family, receptor autophosphorylation and activation of signalling pathways, which regulate cell proliferation, survival and transformation (Citri and Yarden, 2006). A major EGFR signalling route, the mitogen-activated protein kinases (MAPK) pathway is often deregulated in cancer cells. The activation of this pathway, comprised by Ras, Raf, MEK1/2 and extracellular signal-regulated kinase (ERK)1...