The Importance of ERBB Receptor Tyrosine Kinase Signaling in Colorectal Cancer---Implications for EGFR-targeted Therapies
ProQuest, 2007 - 146 pages
Colorectal cancer (CRC) is one of the leading causes of cancer-related death in the United States. Our current understanding of the molecular pathways associated with this malignancy has led to the development of novel molecule targeted therapies, exemplified by small molecule inhibitors and monoclonal antibodies targeting the epidermal growth factor receptor (EGFR/ERBB1). EGFR is a member of the ERBB family of receptor tyrosine kinases consisting of EGFR(ERBB1), ERBB2, ERBB3 and ERBB4. They are transmembrane receptors to elicit cellular signaling pathways in response to extracellular stimuli. Upon ligand binding, ERBB family receptors dimerize to phosphorylate the cytoplasmic kinase domain, resulting in activation of complex downstream signaling cascades, among which the RAS/MEK/MAPK pathway delivers pro-proliferative signals and the PI3K/ATK/mTOR cascade act as a pro-survival pathway. The ERBB family members play a pivotal role in many aspects of cellular biology. As such, misregulation or dysfunction of ERBB receptors has been implicated in many disease states, in particular cancers of epithelial tissues, making the ERBB pathways valuable targets for pharmacological inhibition in cancer treatment. For EGFR-targeted therapies, although preclinical and early clinical studies presented encouraging results, the large-scale clinical trials clearly demonstrate that the majority of patients do not respond. This discrepancy demonstrates that little is known about the mechanisms underlying tumor response to EGFR-targeted therapies. In this study, by using ApcMin mouse models of familial CRC, we generated mice with Egfr deletion exclusively in the intestinal epithelium and demonstrated that although EGFR signaling is critical for establishment of most intestinal tumor, tumors can arise independent of EGFR activity. Moreover, we identified gene expression signatures of EGFR-independent tumors and provided evidence for ERBB3 activity in mediating compensatory pathways. Consequently, we further established the importance of ERBB3 pathway during intestinal tumorigenesis with both ApcMin mouse models of familial CRC and azoxymethane (AOM) model of sporadic CRC. Finally, by utilizing mice harboring a hypomorphic Egfr allele on four different strain backgrounds, we demonstrated the strong background modulation of tumor response to EGFR inhibition. These studies may advance understanding of ERBB biology during intestinal tumorigenesis and help design better therapies in combination with EGFR-targeted agents.
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Exploring the Role of Bacteria in Viral Reactivation and Pathogenesis
Ro Shauna S. Rothwell
No preview available - 2008
adenoma allele analysis antibody ApcMin mice ApcMin mouse model ApcMin polyps ApcMin tumors apoptosis azoxymethane B6-ApcMin BTBR cancer cells Cetuximab colon cancer colonic tumors colorectal cancer deficient deletion downstream effect EGFR inhibition EGFR signaling Egfr wildtype EGFR-independent tumor growth EGFR-targeted therapies Egfr+ Egfrwa2 allele epidermal growth factor epithelium ERBB family members ERBB2 ERBB2 and ERBB3 ERBB3 ERBB3 signaling ERBB3-deficient ERBB3-dependent signaling Erlotinib F1 hybrids Familial adenomatous polyposis gefitinib gene expression genetic background genotype growth factor receptor heterodimer human CRC independently of EGFR inhibitors intestinal epithelium intestinal polyps intestinal tumor intestinal tumorigenesis kinase activity ligand MAPK MAPK activity mice developed molecular Mom1 mutations NSCLC number of polyps phenotype phosphorylation PI3K/AKT polyp number protein RAS-MAPK pathway receptor tyrosine kinases reduced EGFR activity response to EGFR signaling pathways Smad3 small intestine sporadic CRC studies subset tissues tumor multiplicity tumor number tumor response Vil-Cre Villin-Cre wildtype wildtype Egfr