Abstract A34: Arf suppresses the growth and progression of Kras-driven lung tumors

Non-small cell lung carcinoma (NSCLC) is among the deadliest of human cancers, with an overall five-year survival rate of 10–20%. Activating mutations in the Kras proto-oncogene occur in approximately one-third of NSCLC patients, but tumor suppression in the lung remains poorly elucidated. The Cdkn2a locus, which houses both the p16 lnk4a and Arf tumor suppressor genes, is frequently altered in NSCLC; however, the specific role of Arf in lung tumorigenesis has not been well characterized. Several lines of evidence indicate that Kras and other oncogenes induce the expression of Art, which in turn stabilizes p53 activity and arrests the growth of transformed cells. To determine the extent to which Arf suppresses NSCLC development in vivo, we employed the urethane chemical carcinogenesis model of Kras -driven NSCLC. We treated both wild-type and Arf -deficient mice with urethane and found that early-stage lung adenomas in wild-type mice robustly expressed Arf, In contrast to adenomas, malignant lung adenocarcinomas exhibited little induction of Art. Moreover, Arf -deficient mice exposed to urethane displayed accelerated lung tumor-associated morbidity and significantly increased lung tumor size compared to Arf wild-type and heterozygous littermates. Malignant progression of adenomas to adenocarcinomas was also markedly elevated in Arf -deficient mice. These data demonstrate that Arf functions as a barrier to tumor promotion and progression in a carcinogen model of Kras -driven NSCLC. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the Second AACR International Conference on Frontiers in Basic Cancer Research; 2011 Sep 14-18; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2011;71(18 Suppl):Abstract nr A34.