Epidermal growth factor receptor (EGFR) is expressed, albeit at low or intermediate levels, in human melanomas at the different stages of tumor progression. Coexpression of EGFR with its ligand TGFalpha indicates their role in paracrine and autocrine growth regulation of melanomas. As it was previously observed for several types of cancer, specific inhibitors of EGFR-mediated signaling may reduce antiapoptotic properties of cancer cells and sensitize them to cytotoxic drugs. We recently reported that arsenite, particularly in combination with inhibitors of the PI3K-AKT and mitogen-activated protein kinase (MAPK) kinase (MEK)-extracellular signal-regulated kinase (ERK) pathways, induces high levels of apoptosis in different melanomas. Since EGFR signaling operates via activation of the PI3K-AKT and MEK-ERK pathways, we suggested that the combination of arsenite and EGFR inhibitors might also effectively induce apoptosis in melanoma. Here, we demonstrate that a moderate concentration of arsenite (5-10 muM) indeed upregulates apoptosis induced by EGFR inhibitors in EGFR-positive melanomas. In contrast, induction of apoptosis in melanomas with negligible surface expression of EGFR or with defective EGFR signaling requires direct suppression of the PI3K-AKT and MAPK pathways by specific pharmacological inhibitors in the presence of arsenite. Under these conditions, metastatic melanoma cell lines undergo TNF-related apoptosis-inducing ligand (TRAIL)- and tumor necrosis factor alpha (TNFalpha)-mediated apoptosis. Taken together, these data provide additional approaches in sensitizing melanomas to the cytotoxic effects of specific inhibitors of survival pathways.