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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA092479-09
Application #
8016074
Study Section
Molecular Oncogenesis Study Section (MONC)
Program Officer
Salnikow, Konstantin
Project Start
2001-06-01
Project End
2013-01-31
Budget Start
2011-02-01
Budget End
2012-01-31
Support Year
9
Fiscal Year
2011
Total Cost
$278,007
Indirect Cost
Name
North Carolina State University Raleigh
Department
Genetics
Type
Schools of Earth Sciences/Natur
DUNS #
042092122
City
Raleigh
State
NC
Country
United States
Zip Code
27695
Scheving, Lawrence A; Zhang, Xiuqi; Stevenson, Mary C et al. (2015) Loss of hepatocyte EGFR has no effect alone but exacerbates carbon tetrachloride-induced liver injury and impairs regeneration in hepatocyte Met-deficient mice. Am J Physiol Gastrointest Liver Physiol 308:G364-77
Scheving, Lawrence A; Zhang, Xiuqi; Stevenson, Mary C et al. (2015) Loss of hepatocyte ERBB3 but not EGFR impairs hepatocarcinogenesis. Am J Physiol Gastrointest Liver Physiol 309:G942-54
Song, Xiaoling; Fan, Pang-Dian; Bantikassegn, Amlak et al. (2015) ERBB3-independent activation of the PI3K pathway in EGFR-mutant lung adenocarcinomas. Cancer Res 75:1035-45
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 TGFβ-dependent renal fibrosis. J Am Soc Nephrol 23:215-24
Ardito, Christine M; Grüner, Barbara M; Takeuchi, Kenneth K et al. (2012) EGF receptor is required for KRAS-induced pancreatic tumorigenesis. Cancer Cell 22:304-17
Rinella, Erica S; Threadgill, David W (2012) Efficacy of EGFR inhibition is modulated by model, sex, genetic background and diet: implications for preclinical cancer prevention and therapy trials. PLoS One 7:e39552
Franzke, Claus-Werner; Cobzaru, Cristina; Triantafyllopoulou, Antigoni et al. (2012) Epidermal ADAM17 maintains the skin barrier by regulating EGFR ligand-dependent terminal keratinocyte differentiation. J Exp Med 209:1105-19
Eversley, Chevonne D; Yuying, Xie; Pearsall, R Scott et al. (2012) Mapping six new susceptibility to colon cancer (Scc) loci using a mouse interspecific backcross. G3 (Bethesda) 2:1577-84

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