Abstract 1118: Role of the type I insulin-like growth factor receptor in lung tumorigenesis

Abstract

Abstract Lung cancer is the leading cause of cancer related mortalities worldwide. The type I insulin-like growth factor receptor (IGF-IR) is frequently expressed at high levels in lung cancer. This receptor is involved in cell proliferation, apoptosis, migration and differentiation and is emerging as a potential target for molecular therapies. Furthermore, IGF-IR downregulation has been reported to sensitize cancer cells to agents that promote apoptosis. To investigate the importance of the IGF-IR in lung tumorigenesis, our lab generated doxycycline-inducible transgenic mice in which the IGF-IR was overexpressed in type II alveolar or Clara cells. IGF-IR overexpression was sufficient to induce lung tumor development in these mice indicating that this receptor has an important function in the initiation of lung tumorigenesis. To further investigate the role of IGF-IR in lung tumorigenesis, the levels and function of IGF-IR were evaluated in two human lung tumor cell lines (A549 and NCI-H358) and one murine lung tumor cell line (LA-4) as well as in human and murine normal bronchial epithelial cells. Western blotting revealed increased levels of IGF-IR in the lung cancer cell lines compared to the normal lung epithelial cells lines. The efficacy of the IGF-IR small-molecule inhibitor, BMS-754807, which is a drug currently in clinical trials, was also evaluated in the lung tumor cells. BMS-754807 inhibited A549, NCI-H358 and LA-4 cell survival in a dose-dependent manner with approximate IC50 concentrations of 1.70uM for A549, 1.25uM for NCI-H358 and 0.74uM for LA-4 cells. The effects of BMS-754807 on cell proliferation (Ki67 immunofluorescence), cell survival (JC-1 immunofluorescence) and migration (scratch wound and Boyden chamber assays) are currently being examined to determine which properties are affected by disruption of IGF-IR signaling. Similar studies will be performed following downregulation of IGF-IR expression using RNAi. To evaluate whether BMS-754807 could sensitize lung tumor cells to the cytotoxic effects of chemotherapeutic agents commonly employed in the treatment of human lung cancer, BMS-754807 was combined with cisplatin and with carboplatin. Neither the BMS-754807/cisplatin nor the BMS-754807/carboplatin combinations appeared to have a synergistic effect on cell survival. Combinations of BMS-754807 and lung cancer chemotherapeutic agents that do not target DNA are currently being evaluated. Additionally, key downstream molecules of the IGF-IR, including Akt and ERK1/2, are being studied as well as the transcription factor, KLF5, which is expressed at high levels in the lung tumors of the IGF-IR transgenic mice. Initial results support the importance of IGF-IR signaling in lung cancer. Further understanding of the function of IGF-IR in lung cancer will enable the development of more effective targeted therapies and improve existing therapeutic strategies. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1118. doi:10.1158/1538-7445.AM2011-1118