Colorectal cancer (CRC) is the fourth most frequently diagnosed cancer and accounts for the second largest number of cancer deaths in Western societies. One of the major molecular targets to arrise over the last decade is the epidermal growth factor receptor (EGFR), a major mitogenic signal receptor used by many epithelial cell types. Supporting the importance of EGFR in CRC development, we and others have observed that inhibition of EGFR dramatically attenuates development of intestinal and colorectal tumors in the ApcMin mouse model. Yet, some tumors still arise, even with significant reductions in EGFR activity, implying the existence of compensatory mechanisms for the loss of EGFR. This observation is particularly relevant to human cancer therapy since no validated biomarkers or unique gene expression signatures exist that can partition CRCs based upon their likely sensitivity to EGFR inhibitors. Mouse models offer the potential to define the context and biomarkers for tumors likely to respond to EGFR inhibitor therapy. Equally importantly, mouse models have the potential to identify compensatory signaling networks utilized in the context of reduced EGFR activity, which will make excellent therapeutic targets for cancers resistant to EGFR inhibitor therapy. Other Egfr/Erbb-related genes are also expressed in CRCs, driving the development of pan-ERBB inhibitor therapies. However, scant data exists defining the in vivo functional role of Erbb genes during CRC development or their relationship to EGFR during tumorigenesis. We are uniquely positioned to address many of these open questions by exploiting several new mouse models we developed. These models are ideally suited to develop a gene expression biomarker for sensitivity to EGFR inhibition, to investigate the compensatory networks used by cancers when EGFR is inhibited, identifying leads for new therapeutic targets in cancers resistant to anti-EGFR therapy, and to expose the role and functional interactions among the Erbb genes during CRC development.

Public Health Relevance

The identification of biomarkers that indicate which patients will respond to specific molecular-targeted therapies like those against EGFR is highly significant and relevant to improving the efficacy of clinical treatments. Similarly, the identification of pathways that compensate for the loss of targeted pathways offers in targets to improve therapeutic benefit. The use of novel mouse models as proposed in this application has the potential to provide these insights.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
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Molecular Oncogenesis Study Section (MONC)
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Salnikow, Konstantin
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North Carolina State University Raleigh
Schools of Earth Sciences/Natur
United States
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Scheving, Lawrence A; Zhang, Xiuqi; Garcia, Oscar A et al. (2014) Epidermal growth factor receptor plays a role in the regulation of liver and plasma lipid levels in adult male mice. Am J Physiol Gastrointest Liver Physiol 306:G370-81
Rinella, Erica S; Bankaitis, Eric D; Threadgill, David W (2012) Dietary calcium supplementation enhances efficacy but also toxicity of EGFR inhibitor therapy for colon cancer. Cancer Biol Ther 13:130-7
Chen, Jianchun; Chen, Jian-Kang; Nagai, Kojiro et al. (2012) EGFR signaling promotes TGFýý-dependent renal fibrosis. J Am Soc Nephrol 23:215-24
Lee, Daekee; Yu, Ming; Lee, Eunjung et al. (2009) Tumor-specific apoptosis caused by deletion of the ERBB3 pseudo-kinase in mouse intestinal epithelium. J Clin Invest 119:2702-13
Fiske, William H; Threadgill, David; Coffey, Robert J (2009) ERBBs in the gastrointestinal tract: recent progress and new perspectives. Exp Cell Res 315:583-601
Uronis, Joshua M; Threadgill, David W (2009) Murine models of colorectal cancer. Mamm Genome 20:261-8
Lee, Tang-Cheng; Threadgill, David W (2009) Generation and validation of mice carrying a conditional allele of the epidermal growth factor receptor. Genesis 47:85-92
Barrick, Cordelia J; Roberts, Reade B; Rojas, Mauricio et al. (2009) Reduced EGFR causes abnormal valvular differentiation leading to calcific aortic stenosis and left ventricular hypertrophy in C57BL/6J but not 129S1/SvImJ mice. Am J Physiol Heart Circ Physiol 297:H65-75
Barrick, Cordelia J; Yu, Ming; Chao, Hann-Hsiang et al. (2008) Chronic pharmacologic inhibition of EGFR leads to cardiac dysfunction in C57BL/6J mice. Toxicol Appl Pharmacol 228:315-25
Radiloff, Daniel R; Rinella, Erica S; Threadgill, David W (2008) Modeling cancer patient populations in mice: complex genetic and environmental factors. Drug Discov Today Dis Models 4:83-88

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