Abstract
K-ras mutations are associated with smoking-induced lung cancer and poor clinical outcomes. In mice, K-ras mutations are sufficient to induce lung tumors, which require phosphoinoside-3-kinase (PI3K) and further downstream, mammalian target of rapamycin (mTOR) activation. However, the roles of individual Akt isoforms that link PI3K and mTOR are unknown. Here, we show that deletion of Akt1 but not Akt2 or Akt3 prevents lung tumorigenesis in a tobacco carcinogen-induced model and a genetic model. Akt1 deletion prevented tumor initiation as well as tumor progression, coincident with decreased Akt signaling in tumor tissues. In contrast, deletion of Akt3 increased tumor multiplicity in the carcinogen model and increased tumor size in the genetic model. Fibroblasts lacking Akt1 are resistant to transformation by mutant K-ras and stimulation by epidermal growth factor. Human lung cancer cells with mutant K-ras and diminished Akt1 levels fail to grow in vivo. These data suggest that Akt1 is the primary Akt isoform activated by mutant K-ras in lung tumors, and that Akt3 may oppose Akt1 in lung tumorigenesis and lung tumor progression. Given that Akt inhibitors in clinical development as cancer therapeutics are not isoform selective, these studies support specific targeting of Akt1 to mitigate the effects of mutant K-ras in lung cancer.