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

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.

• Authors: Luni Emdad, Irina V Lebedeva, Zao-Zhong Su, Pankaj Gupta, Devanand Sarkar, Jeffrey Settleman, Paul B Fisher
• Journal: Journal of cellular physiology (J Cell Physiol) Vol. 210 Issue 2 Pg. 549-59 (Feb 2007) ISSN: 0021-9541 [Print] United States
• PMID: 17111370 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Enzyme Inhibitors
• Interleukins
• Quinazolines
• interleukin-24
• Epidermal Growth Factor
• eIF-2 Kinase
• Gefitinib

Topics

• Adenoviridae (genetics)
• Adenoviridae Infections (genetics)
• Antineoplastic Agents (pharmacology)
• Apoptosis (drug effects, genetics)
• Carcinoma, Non-Small-Cell Lung (drug therapy, genetics, metabolism)
• Cell Line, Tumor
• Drug Resistance, Neoplasm (genetics)
• Enzyme Inhibitors
• Epidermal Growth Factor (genetics, metabolism)
• Gefitinib
• Gene Expression Regulation, Neoplastic (drug effects, genetics)
• Genetic Therapy (methods)
• Genetic Vectors (genetics, pharmacology)
• Humans
• Interleukins (genetics)
• Lung Neoplasms (drug therapy, genetics, metabolism)
• Mutation (genetics)
• Quinazolines (pharmacology)
• eIF-2 Kinase (antagonists & inhibitors, genetics, metabolism)