Pancreatic cancer is genetically complex, and without effective
therapy. Mutations in the Kirsten-ras (K-ras) oncogene occur early and frequently (approximately 90%) during
pancreatic cancer development and progression. In this context, K-ras represents a potential molecular target for the
therapy of this highly aggressive
cancer. We now show that a bipartite adenovirus expressing a novel
cancer-specific apoptosis-inducing
cytokine gene, mda-7/
interleukin-24 (IL-24), and a K-ras AS gene, but not either gene alone, promotes growth suppression, induction of apoptosis, and suppression of
tumor development mediated by K-ras mutant
pancreatic cancer cells. Equally, the combination of an adenovirus expressing mda-7/IL-24 and pharmacologic and genetic agents simultaneously blocking K-ras or downstream extracellular regulated
kinase 1/2 signaling also promotes similar inhibitory effects on the growth and survival of K-ras mutant
pancreatic carcinoma cells. This activity correlates with the reversal of a translational block in mda-7/IL-24
mRNA in
pancreatic cancer cells that limits message association with polysomes, thereby impeding translation into
protein. Our study provides support for a "dual
molecular targeted therapy" involving oncogene inhibition and selective
cancer apoptosis-inducing gene expression with potential for effectively treating an invariably fatal
cancer.