| The epidermal growth factor receptor (EGFR) is a cell surface, transmembrane tyrosine kinase receptor that modulates the development and pathology of most tissues of the body. The classical mouse mutation Egfrwa2 (waved2) produces a receptor with reduced kinase activity that supports survival through adulthood, allowing examination of phenotypes resulting from EGFR activity deficiency in adults. Adult Egfr wa2 homozygotes on congenic or hybrid backgrounds exhibit a variety of subtle or low penetrance phenotypes in a strain-dependent manner, including reduced survival, runting, macrocytic anemia, circadian-related activity differences, seizures, altered acoustic startle, and abnormalities in skin, eye, heart and skeleton. The Egfrwa2 allele was additionally used to genetically examine the consequences of reduced EGFR activity on the ApcMin mouse model of intestinal tumorigenesis. A dramatic loss of polyps was found on the Egfrwa2 background between initiation and expansion stages of tumor development, suggesting an intermediate establishment phase requiring normal EGFR activity for polyp survival. Further analysis of ApcMin polyps demonstrates two compartments of altered EGFR signaling, with transformed cells exhibiting heightened EGFR phosphorylation and normal tumor-associated epithelium heightened total EGFR levels. Additionally, all known EGFR ligands are upregulated within ApcMin polyps, and EGFR localization and activity are altered in two other mouse models of intestinal cancer. Pharmacological reduction of EGFR activity in ApcMin polyps and carcinoma xenografts support a positive role for EGFR activity in intestinal tumorigenesis. Taken together, the tumorigenesis studies demonstrate complex requirements for EGFR activity for tumor survival, including alterations in EGFR biology in normal tissue associated with tumors. Finally, defects found in Egfrwa2 mice mirror the toxicity seen in human patients on EGFR-inhibition therapy, as do defects found in other mouse models for toxicity resulting from their respective targeted therapies. These observations suggest the use of mouse models as potent tools to predict novel toxicity from newly emerging targeted therapies, as well as to dissect the underlying biology of toxicity susceptibility. |
