title: Targeted combinatorial therapy of non-small cell lung carcinoma using a GST-fusion protein of full-length or truncated MDA-7/IL-24 with Tarceva.
abstract: Melanoma differentiation associated gene-7/interleukin-24 (mda-7/IL-24), a cytokine belonging to the IL-10 family, displays cancer-specific apoptosis-inducing properties when delivered by a replication-incompetent adenovirus (Ad.mda-7) or as a GST-tagged recombinant protein (GST-MDA-7). Previous studies demonstrated that an adenovirus expressing M4, a truncated version of MDA-7/IL-24 containing amino acid residues 104-206, also induced similar cancer-specific apoptosis. We generated recombinant GST-M4 proteins and examined the potency of GST-MDA-7 and GST-M4 on a panel of epidermal growth factor receptor (EGFR) wild type and mutant non-small cell lung carcinoma (NSCLC) cells either as a single agent or in combination with a reversible EGFR inhibitor, Tarceva. The combination of either GST-MDA-7 or GST-M4 ( approximately 0.1 microM) and Tarceva (10 microM), at sub-optimal apoptosis-inducing concentrations synergistically enhanced growth inhibition and apoptosis induction over that observed with either agent alone. The combination treatment also augmented inhibition of EGFR signaling, analyzed by phosphorylation of EGFR and its downstream effectors AKT and ERK1/2, over that with single-agent therapy. Tarceva enhanced GST-MDA-7 and GST-M4 toxicity in cells expressing mutated EGFR proteins that are resistant to the inhibitory effects of Tarceva. In total, these data suggest that combined treatment of NSCLC cells with an EGFR inhibitor can augment the efficacy of GST-MDA-7 and GST-M4 and that the EGFR inhibitor Tarceva may mediate this combinatorial effect by inhibiting multiple tyrosine kinases in addition to the EGFR. This approach highlights a potential new combinatorial strategy, which may prove beneficial for NSCLC patients with acquired resistance to EGFR inhibitors.
authors.affiliation: Department of Urology, Herbert Irving Comprehensive Cancer Center, Columbia University, College of Physicians and Surgeons, New York, New York 10032, USA.
authors.forename: Pankaj
authors.initials: P
authors.lastname: Gupta
authors.forename: Luni
authors.initials: L
authors.lastname: Emdad
authors.forename: Irina V
authors.initials: IV
authors.lastname: Lebedeva
authors.forename: Devanand
authors.initials: D
authors.lastname: Sarkar
authors.forename: Paul
authors.initials: P
authors.lastname: Dent
authors.forename: David T
authors.initials: DT
authors.lastname: Curiel
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Settleman
authors.forename: Paul B
authors.initials: PB
authors.lastname: Fisher
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004357:Drug Synergism; D004789:Enzyme Activation / Q000187:drug effects; D066246:ErbB Receptors / Q000037:antagonists & inhibitors; D000069347:Erlotinib Hydrochloride; D049452:Green Fluorescent Proteins / Q000302:isolation & purification / Q000378:metabolism*; D006801:Humans; D007378:Interleukins / Q000302:isolation & purification / Q000627:therapeutic use*; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D020935:MAP Kinase Signaling System / Q000187:drug effects; D050505:Mutant Proteins / Q000302:isolation & purification / Q000627:therapeutic use*; D009928:Organ Specificity / Q000187:drug effects; D011799:Quinazolines / Q000494:pharmacology / Q000627:therapeutic use*; D011993:Recombinant Fusion Proteins / Q000302:isolation & purification / Q000627:therapeutic use*; D014410:Tumor Stem Cell Assay; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism; D000099180:Interleukin-24
chemical_list: D000970:Antineoplastic Agents; D066246:ErbB Receptors; D000069347:Erlotinib Hydrochloride; D049452:Green Fluorescent Proteins; D007378:Interleukins; D050505:Mutant Proteins; D011799:Quinazolines; D011993:Recombinant Fusion Proteins; D048051:p38 Mitogen-Activated Protein Kinases; D000099180:Interleukin-24