The Importance of the Insulin-like Growth Factor Signaling Pathway in Lung Cancer and the Potential of its Components as Therapeutic Targets
Lung cancer is the leading cause of cancer-related mortalities worldwide. Despite the introduction of new therapeutics, there has been very little improvement in survival for patients with advanced stage disease. The insulin-like growth factor (IGF) system is frequently activated in lung cancer and the type I insulin-like growth factor receptor (IGF-IR) has emerged as a potential therapeutic target. However, clinical trials to date have had limited success and it is clear that a more thorough understanding of the IGF-system is required to improve clinical efficacy in targeting this pathway. Here we show that treatment with a dual inhibitor that targets the IGF-IR and the insulin receptor decreased proliferation and survival of lung cancer cells, which was mediated by inhibition of Akt signaling. Furthermore, use of the dual inhibitor enhanced the effects of low doses of platinum therapeutics in lung cancer cells. Akt is an important mediator of IGF-IR signaling and is currently under investigation as a therapeutic target in its own right. Akt exists as three isoforms (Akt1-3), which were previously thought to be largely redundant in activity; however, recent evidence indicates that they have unique functions. In order to investigate the specific roles of Akt isoforms in lung tumorigenesis our lab used a previously developed tissue-specific, inducible transgenic mouse model of lung cancer. In these mice, IGF-IR overexpression in type II alveolar cells is sufficient to induce the formation of nodular adenomas and adenocarcinomas. By combining these transgenic mice with isoform specific Akt knockout mice, we were able to determine if the lack of a single Akt isoform was sufficient to disrupt lung tumorigenesis. Akt1 deficiency was sufficient to decrease IGF-IR-mediated lung tumor development resulting in fewer surface tumors and a lower tumor burden but having no influence in tumor histology. In contrast, Akt2 deficient mice had an increase in tumor burden as well as a change in tumor histology. These mice had diffuse tumor tissue throughout their lungs as tumors did not maintain nodular growth. Therefore, Akt isoforms have unique roles in IGF-IR mediated lung tumorigenesis, which should be reflected in the design and implementation of Akt-targeting therapeutics.