Abstract B11: Foxm1 mediates maintenance and progression of mouse lung tumor driven by oncogenic Kras

Abstract

Abstract Oncogenic mutation of Kras gene is one of the major causes of non-small cell lung cancer (NSCLC), and there is no effective chemotherapy agent available for targeting cancers harboring oncogenic Kras mutations. Hence, identifying new downstream molecular targets of KRAS signaling is critical for improving current therapeutic outcomes. Previous research has demonstrated that increased activity and expression of Forkhead box M1 (FOXM1) transcription factor are associated with poor prognosis in NSCLC patients. We and others have reported that FOXM1 regulates gene transcription network of cell cycle, angiogenesis, epithelial-to-mesenchymal transition (EMT), cell migration, and cancer stemness. Deletion of Foxm1 alleles in respiratory epithelial cells diminished the lung tumor initiation in SPC-rtTA/tetO-KrasG12D/Foxm1-/- mice; however, whether Foxm1 is critical for Kras mutant tumor maintenance and progression remains unclear. Herein, we report that intratracheal (IT) injected adenoviral Ad-Cre to CCSP-rtTA/tetO-KrasG12D/Foxm1fl/fl mice that bear induced KRAS mutant lung tumors, causing 75% of preexisting lung tumor regression as detected by micro-computed tomography (μCT). IT treatment with Ad-Cre that mediated genetically deletion of Foxm1 alleles in lungs, resulted in reduced proliferation of tumor cells. Moreover, in vitro disruption of FOXM1 expression by shRNA diminished cell proliferation on plate and anchorage-independent growth in soft agar of KRAS-mutated lung cancer NCI-H23 as well as KRASG12D-transformed BEAS-2B cells. Accordingly, these results demonstrated that Foxm1 is critical for oncogenic KRAS signaling pathway in both maintenance and progression of lung adenocarcinoma, suggesting that Foxm1 could be a potential therapeutic target to improve the outcome of KRAS mutant lung cancer treatment. Citation Format: Sheng-Yang Chao, Chien-Cheng Li, Sheng-Kai Liang, Yi-Shiuan Chiu, Yi-Kai Lin, Chia-Chan Hsu, Jen-Kun Chen, Tsui-Chun Tsou, I-Ching Wang. Foxm1 mediates maintenance and progression of mouse lung tumor driven by oncogenic Kras [abstract]. In: Proceedings of the AACR Special Conference: Advances in Modeling Cancer in Mice: Technology, Biology, and Beyond; 2017 Sep 24-27; Orlando, Florida. Philadelphia (PA): AACR; Cancer Res 2018;78(10 Suppl):Abstract nr B11.