Abstract Genetically engineered mouse (GEM) models of human cancer provide important insights into mechanisms of disease development. Colorectal cancer is a common malignancy, whereas small intestinal cancer is much less frequent. We recently developed a mouse model of colonic neoplasia, using the highly efficient inducible stem cell driver, leucine-rich repeats and immunoglobulin-like domains protein 1 (Lrig1CreERT2), and a floxed allele of the tumor suppressor gene, adenomatous polyposis coli (Apcfl/+) (Cell 149: 146-158, 2012). Lrig1CreERT2/+;Apcfl/+ mice develop multiple, large highly dysplastic adenomas in the distal colon within 50 days of tamoxifen induction; the proximal colon is spared and smaller tumors are detected in the small intestine. We hypothesized an additional oncogenic event would advance tumorigenesis in this model. To investigate this hypothesis, using a Kras mutation (G12D) as the second event, we developed a new inducible mouse model: Lrig1CreERT2/+;Apcfl/+;KrasLSL-G12D/+. Due to broad Lrig1 expression, systemic Kras activation through intraperitoneal tamoxifen injection results in debilitating oral and facial tumors within three to five weeks, precluding longer-term intestinal studies. To overcome the rapid onset of this phenotype, we administered 4-hydroxytamoxifen (4-OHT) enemas to achieve local tamoxifen delivery. This method delayed onset of oral tumor development, even preventing it in some mice. However, we noted Lrig1CreERT2/+;Apcfl/+;KrasLSL-G12D/+ mice rarely developed colonic tumors, compared to Lrig1CreERT2/+;Apcfl/+ control mice. We hypothesized Kras activation before complete Apc loss of heterozygosity provides a barrier to tumor formation. Therefore, we administered 4-OHT enemas to Lrig1CreERT2/+;Apcfl/fl;KrasLSL-G12D/+ mice to determine whether Kras activation could advance tumorigenesis in the setting of loss of both Apc alleles. In a preliminary experiment, we observed that Kras activation caused a more severe phenotype in the colonic epithelium of Lrig1CreERT2/+;Apcfl/fl mice compared to Lrig1CreERT2/+;Apcfl/fl control mice. Both genotypes developed skin lesions that affected the health of animals, requiring sacrifice as early as 28 days after tamoxifen administration. Further characterization of this model will determine whether invasion in the colonic lesions can occur under these genetic conditions. Citation Format: Emily Poulin. Using Lrig1CreERT2/+ stem cell driver mice to model colorectal 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 B12. doi: 10.1158/1557-3125.RASONC14-B12