Abstract 1612: Investigating NF-κB pathway as a novel therapeutic target in preclinical lung cancer mouse models

Abstract

Abstract Lung cancer represents the most frequent cancer type and the leading cause of cancer death (1.3 million worldwide). Non-small cell lung cancer (NSCLC) accounts for 80% of all lung cancer cases. NSCLC development is associated with frequent mutations in well-defined oncogenes and tumor suppressor genes such as Kras (30%) and p53 (50-70%). We recently demonstrated that hyper-activated NF-kB pathway in NSCLC is required for the initiation and maintenance of lung cancer, indicating this pathway as a promising therapeutic target. In this study, we tested therapeutic delivery of proteasome inhibitor Bortezomib (Velcade) to inhibit NF-κB pathway in NSCLC mouse models. In mouse lung cancer cell lines harboring KrasG12D and p53 loss (KP cells), Bortezomib efficiently reduced nuclear p65, repressed NF-kB target genes such as Bcl2 and rapidly induced apoptosis. The cell lines with high NF-kB activity are especially sensitive to Bortezomib. Using autochothonous mouse models and microCT imaging, we showed that Bortezomib treatment at a well-tolerated dose leads to lung tumor regression in mice and prolonged survival. Our results demonstrated using preclinical mouse models to study cancer treatment response and supported NF-kB pathway as an effective therapeutic target in lung cancer. 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 1612. doi:10.1158/1538-7445.AM2011-1612