Combinatorial treatment of non‐small‐cell lung cancers with gefitinib and Ad.mda‐7 enhances apoptosis‐induction and reverses resistance to a single therapy

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Abstract
Activation of the epidermal growth factor receptor (EGFR) contributes to the pathogenesis of non‐small‐cell lung carcinomas (NSCLC) and gefitinib, a selective reversible EGFR inhibitor, is effective in treating patients with NSCLC. However, clinical resistance to gefitinib is a frequent occurrence highlighting the need for improved therapeutic strategies. Melanoma differentiation associated gene‐7 (mda‐7)/Interleukin‐24 (IL‐24) (mda‐7/IL‐24) displays cancer‐selective apoptosis induction when delivered via a replication‐incompetent adenovirus (Ad.mda‐7). In this study, the effect of Ad.mda‐7 infection, either alone or in combination with gefitinib, was analyzed in a panel of NSCLC cell lines carrying wild‐type EGFR (H‐460 and H‐2030) or mutant EGFR (H‐1650 and H‐1975). While H‐2030 and H‐1650 cells were sensitive, H‐460 and H‐1975 cells were resistance to growth inhibition by Ad.mda‐7, which was reversed by the combination of Ad.mda‐7 and gefitinib. This combination increased MDA‐7/IL‐24 and downstream effector double‐stranded RNA‐activated protein kinase (PKR) protein expression, promoting apoptosis induction of NSCLC cells. Inhibition of PKR significantly inhibited apoptosis induction by Ad.mda‐7 when administered alone but not when used in combination with gefitinib. The combination treatment also augmented inhibition of EGFR signaling. Our findings indicate that a combinatorial treatment with Ad.mda‐7 and gefitinib may provide benefit in the treatment of NSCLC, especially in patients displaying resistance to clinically used EGFR inhibitors. J. Cell. Physiol. 210: 549–559, 2007.