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.