Abstract 4880: Disruption of STAT3 signaling promotes K-Ras induced lung tumorigenesis

Lung cancer related and unrelated to smoking is still leading cause of cancer deaths worldwide with an overall survival rate of 15%. Several genetic alterations have been associated with lung cancer: loss of tumor suppressor genes such as p53, INK4a, LKB1 and mutations/amplifications in several oncogenes like K-Ras, EGFR, or c-Myc. Most frequent smoking-related mutations impair GTP hydrolysis in K-Ras, an oncogene downstream of the EGFR pathway, causing persistent cell growth and proliferation in 20-30% of lung adenocarcinomas. Another important downstream effector of EGFR signaling is the signal transducer and activator of transcription (STAT)-3. STAT-3 regulates important pathways in tumorigenesis, through upregulation of genes encoding apoptosis inhibitors (Bcl-XL, Bcl-2, Mcl-1, survivin). In patient samples and NSCLC cell lines nuclear, phosphorylated STAT3 is enhanced and correlates with subsequent suppression of apoptosis of NSCLC tumors. However, the role of STAT-3 in lung cancer in vivo has not yet been established. In order to investigate the role of STAT-3 in lung tumors, we have established a genetic mouse model that allows inducing K-RasG12D-dependent lung tumors and simultaneously genetically ablating STAT-3. Survival analysis of this model showed a significant advantage of K-RasG12D male mice harbouring STAT-3 compared to K-RasG12D mice lacking one or both alleles of Stat-3, indicating a hapoloinsufficient tumor suppressor role in oncogenic K-RasG12D tumor formation. Furthermore, animals with deleted STAT-3 and activated K-RasG12D have a significant increase in tumor burden and develop more adenomas and adenocarcinomas than age-matched animals, harbouring only oncogenic K-RasG12D. This data suggest that disruption of STAT-3 signaling promotes tumorigenesis in K-Ras induced tumors. We are currently investigating the molecular and cellular mechanisms responsible for this observation. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4880. doi:1538-7445.AM2012-4880