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It is reported that the agonistic antibodies against death receptors 4 and 5 (DR4, DR5) are cytotoxic to various cancer cells. In the present study, the sensitivity of five human lung cancer cell lines to previously reported AD5-10 agonistic antibody against DR5 were investigated. Of these cell lines, A549 and small cell lung cancer showed a moderate sensitivity to AD5-10 and three other cell lines were resistant. Cell line H460 is resistant to AD5-10 despite a high level of cell-surface DR5 expression. We demonstrated that the resistance of H460 cells to AD5-10 was not related to the expression level of DR5, but the expression and cleavage of c-FLIPL in the cells. Inhibition of endogenous c-FLIPL expression by siRNA significantly enhanced AD5-10-induced cell death in these lung cancer cells. We further showed that this sensitizing effect was associated with decreased expression of Bcl-2 family proteins Bid and Bcl-XL, change of mitochondrial membrane potential, release of cytochrome c from mitochondria, and caspase activation. Therefore, these data provide evidence that c-FLIPL is involved in the resistance of lung cancer cells to AD5-10-induced apoptosis. Moreover, immunohistochemistry on paraffin-embedded tissue revealed that c-FLIPL was expressed in 87.9% (29 of 33) of lung carcinoma tissues from the patients, but little in tissues from normal controls. This suggests that inhibition of c-FLIPL expression might be a potential strategy for lung cancer therapy, especially for those lung cancers resistant to the agonistic antibody against death receptors. (Cancer Sci 2009; 100: 940–947)