Abstract 2799: Development of a mouse model of KRAS mutated colorectal cancer tumorigenesis

Abstract

Abstract Introduction Development of a preclinical animal model that mimics KRAS mutated colorectal cancer disease etiology is essential for validation of new therapeutic interventions. Colorectal cancer patients with tumors harboring KRAS mutation are excluded from receiving anti EGFR monoclonal antibodies, and currently have no alternate FDA approved treatment options available. Ongoing research requires validations of different modalities on a robust preclinical study platform that will resemble the disease phenotype and genetic profile. In this context we have developed viable animal mouse model of colorectal cancer bearing KRAS mutation that authentically serves as a model for the disease. Methodology: The C57 BL/6 mice with truncated APC floxed allele was crossed with heterozygous KRAS floxed outbred mice to generate APC f/f KRAS +/f mouse colony. In another set of breeding APC floxed mice were crossed with CDX2-Cre-ERT2 mice and selected for APCf/f CDX2-Cre-ERT2 after second round of inbreeding. The final model of the disease was generated by the cross of the two aforementioned colonies when viable APC f/f KRAS +/f CDX2-Cre-ERT2 were genotyped and characterized. The model animals were tamoxifen induced to generate tumors. Micro-PET scan was used to detect and measure tumor volume. H & E staining was done to establish neoplasm and immunohistochemistry was performed to determine histological similarities with human FFPE biopsies. The MSI/MSS status was also determined. Results Ø The newly developed animal model develops colonic tumors upon induction with Tamoxifen. Ø The tumors were malignant as confirmed by H and E staining. Ø The tumors showed a higher radioactive FDG uptake (SUV) in micro-PET scan Ø The tumors resembled human colorectal cancer tissue Ø Once tumor is generated the animals died of cachexia and rectal bleeding Conclusion: Heterozygous mutation of KRAS oncogene along with deletion mutation of Adenomatous polyposis coli (APC) gene is embryonically lethal in animal models. We have successfully developed a viable animal model of KRAS mutated colorectal cancer with tamoxifen inducible tumors harboring KRAS and APC mutations. The tumors mimic the human disease type both genetically and immunohistochemically. This model can serve as a robust preclinical platform for understanding the disease mechanism at the molecular level as well for evaluation of various therapeutic interventions. Citation Format: Radhashree Maitra, Madhu Kumar Venkatesh, Titto Alby Augustine, Carol Chandy, Qiang Liu, Sanjay Goel. Development of a mouse model of KRAS mutated colorectal cancer tumorigenesis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2799. doi:10.1158/1538-7445.AM2017-2799