title: 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.affiliation: Department of Urology, Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, College of Physicians and Surgeons, New York, New York 10032, USA.
authors.forename: Luni
authors.initials: L
authors.lastname: Emdad
authors.forename: Irina V
authors.initials: IV
authors.lastname: Lebedeva
authors.forename: Zao-Zhong
authors.initials: ZZ
authors.lastname: Su
authors.forename: Pankaj
authors.initials: P
authors.lastname: Gupta
authors.forename: Devanand
authors.initials: D
authors.lastname: Sarkar
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Settleman
authors.forename: Paul B
authors.initials: PB
authors.lastname: Fisher
mesh_terms: D000256:Adenoviridae / Q000235:genetics; D000257:Adenoviridae Infections / Q000235:genetics; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D004791:Enzyme Inhibitors; D004815:Epidermal Growth Factor / Q000235:genetics / Q000378:metabolism; D000077156:Gefitinib; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects / Q000235:genetics; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000235:genetics / Q000494:pharmacology; D006801:Humans; D007378:Interleukins / Q000235:genetics*; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D009154:Mutation / Q000235:genetics; D011799:Quinazolines / Q000494:pharmacology*; D019892:eIF-2 Kinase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D000099180:Interleukin-24
chemical_list: D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D004815:Epidermal Growth Factor; D000077156:Gefitinib; D007378:Interleukins; D011799:Quinazolines; D019892:eIF-2 Kinase; D000099180:Interleukin-24