The Model System: SPC-IGFIR Mice
Similar to the MTB-IGFIR transgenic mice, SPC-IGFIR transgenic mice overexpress human IGF-IR in a doxycycline-inducible manner. In the case of SPC-IGFIR transgenic mice, the surfactant protein C (SPC) promoter is used to drive IGF-IR transgene expression in type II alveolar cells. Overexpression of IGF-IR in type II alveolar cells induces lung tumor development in 100% of the mice after 8 months of IGF-IR overexpression. The lung tumors that arise in SPC-IGFIR transgenic mice resemble human lung adenocarcinoma, a subtype of non-small cell lung cancer (NSCLC).
Akt Isoforms in Lung Cancer
In mammals, 3 isoforms of Akt exist, Akt1, Akt2 and Akt3. It was originally thought that these 3 isoforms performed largely redundant functions however emerging data indicates that this is not always the case. In lung tumors of SPC-IGFIR mice, Akt1 and Akt2, but not Akt3 are found at detectable levels. To investigate the effects of Akt1 and Akt2 on lung tumorigenesis, SPC-IGFIR mice were mated with Akt1-/- or Akt2-/- mice.
We found that loss of Akt1 inhibited, while loss of Akt2 promoted, lung tumor development in SPC-IGFIR mice. We also showed that an Akt1 selective inhibitor was more effective at reducing growth/survival of human lung cancer cell lines in vitro than a pan-Akt inhibitor. These findings could have therapeutic implications since only pan-Akt inhibitors are currently being investigated in clinical trials. We are currently evaluating human lung cancer cell lines with different mutation profiles to determine whether Akt1 inhibition is universally more effective or it’s selectivity is restricted to lung cancer cell with particular mutations. We are also evaluating the differences in intracellular signaling following treatment with the pan-Akt inhibitor and Akt1 selective inhibitor.