Abstract 5269: Divergent roles of Akt isoforms in insulin-like growth factor-mediated lung tumorigenesis.

Abstract

Abstract Lung cancer is the leading cause of cancer related mortalities worldwide. Akt is an important kinase in the PI3K pathway of growth factor signaling, and increased Akt activation in lung cancer is associated with poor prognosis. Akt regulates cell growth, proliferation, survival, metabolism and migration making it an attractive target for molecular therapies. Akt exists as three isoforms (Akt1-3) and while it was previously thought they were largely redundant in activity, evidence of differing roles is emerging. Our lab has generated a doxycycline-inducible, tissue-specific transgenic mouse model of lung cancer. Using a surfactant protein C (SPC) promoter, the type I insulin-like growth factor receptor (IGF-IR) is overexpressed in type II alveolar cells which initiates the development of tumors in the lungs. Following nine months of treatment with doxycycline, macroscopic tumors are present on 100% of transgenic mice. These lung adenomas typically present as one or more discrete nodules on the surface of the lung. In this model, cells expressing high levels of IGF-IR also had higher levels of activated Akt. To investigate the role of specific Akt isoforms in lung tumorigenesis, these SPC-IGFIR transgenic mice were crossed with Akt1 null or Akt2 null mice to generate SPC-IGFIR-Akt1-/- and SPC-IGFIR-Akt2-/- mice. The Akt1 null SPC-IGFIR mice have reduced tumor burden compared to their Akt wild-type counterparts. In contrast, the absence of Akt2 accelerates tumor growth in SPC-IGFIR mice. Tumors formed in Akt1 null mice maintain the phenotype of distinct nodules. However, in the advanced tumor progression seen in Akt2 null mice the tumor tissue appears to permeate the lungs rather than form large nodules. These tumors are currently being characterized through evaluation of intracellular signaling as well as rates of proliferation and apoptosis. Initial results indicate opposing roles of Akt1 and Akt2 in the development and progression of lung cancer. While pan-Akt inhibitors are currently in clinical trials, our data suggests targeting Akt1 may be a more effective therapeutic strategy for lung cancer. However, further understanding of the function of each Akt isoform in lung cancer is needed. Citation Format: Sarah Elizabeth Franks, Roger A. Moorehead. Divergent roles of Akt isoforms in insulin-like growth factor-mediated lung tumorigenesis. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5269. doi:10.1158/1538-7445.AM2013-5269