Genetic dissection of mechanisms underlying epidermal growth factor receptor-independent colorectal cancer development
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AbstractColorectal cancer (CRC) is the third most common cancer and second leading cause of cancer-related death in the United States. Substantial effort has gone into understanding molecular mechanisms governing CRC progression with the goal of developing potent targeted therapies. Epidermal growth factor receptor (EGFR) was one of the first molecular targeted therapies. However clinical trials using EGFR inhibitors are not as efficient, suggesting an alternative and independent EGFR-CRC progression mechanism. In this study, we also evaluated the importance of ERBB3, a related EGF receptor, in EGFR-independent colorectal cancer progression. Using intestine-specific genetic ablation of Egfr in the ApcMin/+ (genetic) and axozymethane (carcinogenic) CRC mouse models, we show that 10% of colonic tumors arise independent of EGFR activity. Molecular analysis confirmed the lack of Egfr in these tumors and the formal proof for the existence of an EGFR-independent pathway. Tumors developing in absence of EGFR are larger in size than those developing under normal EGFR activity suggesting that EGFR independent tumors may have a faster growth rate. We also have evidence that ERBB3 may mediate compensatory pathways. Using intestinal specific ablation of Erbb3 (Erbb3f/f) we previously showed that the number of intestinal tumors in the ApcMin/+ model is greatly reduced. Importantly, polyps forming in absence of ERBB3 are significantly smaller than controls, suggesting that normal levels of ERBB3 signaling is essential for tumor growth in the ApcMin/+ model. More recently, we have generated a combinatorial model that conditionally inactivates both Erbb3 and Egfr in the intestinal epithelia. These models will provide powerful tools to genetically dissect molecular pathways contributing to CRC, and aid in identifying molecular biomarkers that can differentiate EGFR-independent from EGFR-dependent CRC. These studies may advance understanding of ERBB biology during colonic tumorigenesis and help design better therapies in combination with EGFR-targeted agents.Citation Format: Carolina Mantilla-Rojas, Ming Yu, David Threadgill. Genetic dissection of mechanisms underlying epidermal growth factor receptor-independent colorectal cancer development. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr LB-039.
