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Chemotherapy with platinum agents is the standard of care for non-small-cell lung cancer (NSCLC); however, novel molecular-targeted agents like gefitinib have been approved for advanced NSCLCs, including recurrent cases previously treated with platinum-based chemotherapy. Although these agents show antitumor activity through distinct mechanisms and elicit positive initial responses, tumors invariably develop resistance. Recent studies have revealed mechanisms by which both types of agents induce acquired resistance. However, little is known about whether first-line treatment with either type of agent affects cancer cell susceptibility and development of resistance against subsequent treatment with the other. Using in vitro drug-resistant NSCLC cell models, we provide evidence that acquired cisplatin resistance may reduce the sensitivity of cancer cells to subsequent treatment with a molecular-targeted agent. In addition, first-line cisplatin treatment influenced the mechanism by which cancer cells developed resistance to subsequent treatment with a molecular-targeted agent. The influence of cisplatin on acquisition of resistance to a molecular-targeted agent was associated with epithelial–mesenchymal transition (EMT)-like alterations such as increased expression of mesenchymal markers, morphological change, and AXL tyrosine kinase-mediated increased cell motility. Our findings indicate that the influence of platinum-based chemotherapy on molecular-targeted therapies and the involvement of EMT and EMT-related effectors should be considered when developing therapeutic strategies using antitumor agents, especially in the context of sequential therapy.