Abstract B09: Loss of PTEN cooperates with mutant KRAS initiating EMT and increased stemness in a mouse model of lung cancer

Abstract

Abstract We have developed a preclinical model of lung cancer associated with hyper-activated PI3K/mTOR and KRAS. Non-small cell lung cancer (NSCLC) accounts for ∼80% of all lung cancers; of which >50% have aberrant PI3K/AKT/mTOR signaling and ∼30% harbor oncogenic KRAS, conferring chemo/radio-resistance and poor prognosis. KRAS inhibitors are difficult to develop, and rapalogs targeting mTOR are toxic and induce compensatory activation of AKT, causing resistance to apoptosis. Hence, development of effective inhibitors of KRAS and PI3K/mTOR pathways is imperative. Further, clinical studies implicate that tumors with aberrant KRAS and PI3K/mTOR signaling are associated with epithelial-mesenchymal transition (EMT), metastasis, poor differentiation, and chemo/radio-resistance. However, molecular details of EMT mediated by KRAS and PI3K/mTOR pathway is lacking, limiting the development of drugs targeting EMT-mediators. Using a CCSP-promoter driven Cre/LoxP mediated deletion of PTEN in an oncogenic KRAS status (PTENΔΔ/KRasG12D), we have developed a preclinical mouse model of lung cancer with hyper-activation of PI3K/mTOR and KRAS pathways. Microarray based RNA profiling followed by bioinformatic analysis on PTEN-null lung epithelial cells revealed transcriptional activation of RAS/RAF/MAPK/ERK pathway associated candidate genes. On the other hand, Dox-induced PTENΔΔ/KRasG12D lung tumors showed induction of SNAIL1, SLUG, ZEB-2 and SOX2 genes. Taken together, our analysis reveals that PTEN loss predisposes lung tumors to hyper-activation of the KRAS pathway, which is further accentuated by oncogenic mutation in KRAS, initiating EMT and increased stemness. Citation Format: Prerna Malaney, Vrushank Dave. Loss of PTEN cooperates with mutant KRAS initiating EMT and increased stemness in a mouse model of lung cancer. [abstract]. In: Proceedings of the AACR Special Conference on RAS Oncogenes: From Biology to Therapy; Feb 24-27, 2014; Lake Buena Vista, FL. Philadelphia (PA): AACR; Mol Cancer Res 2014;12(12 Suppl):Abstract nr B09. doi: 10.1158/1557-3125.RASONC14-B09