Modulation of Survival Pathways in Ovarian Carcinoma Cells Resistant to Platinum Compounds

Alterations of various signaling pathways implicated in cell survival or cell death may have relevance in cancer cell drug resistance. In particular, the EGF-R pathway may affect cellular response to platinum compounds, because these drugs are capable of modulating the signaling occurring through activation of EGF-R or EGF-R-mediated activation of downstream events. Recent evidence indicates that ovarian carcinoma cells selected for resistance to cisplatin and oxaliplatin exhibits decreased sensitivity to gefitinib. The effect appears not dependent on failure to inhibit the target receptor, but is associated with increased phospho-ERK1/2 levels in the resistant variants. Cells resistant to gefitinib also exhibit reduced sensitivity to MEK1/2 inhibitors. The concomitant activation of distinct mitogen-activated protein kinases, i.e., ERK1/2 and p38 appears a relevant feature of cell resistance to cisplatin. Thus, the development of resistance to platinum drugs is associated with multiple alterations including deregulation of survival pathways activated by EGF-R resulting in a reduced Cellular response to gefitinib.