We have investigated whether transforming mutants of the Epidermal Growth Factor Receptor (EGFR), such as EGFRvIII, are regulated by Cbl proteins. We have shown that Cbl proteins can ubiquitinate and down regulate the oncogenic form of the EGFR, EGFRvIII. Our data indicated that the amplification and overexpression of the constitutively active EGFRvIII accounts for its transforming ability and that EGFRvIII does not escape normal negative regulatory mechanisms. In collaboration with Morag Park and Kalle Gehring at McGill University, we have determined the structure of the UBA domain of Cbl-b and shown that Cbl-b dimerizes by binding to ubiquitin and this is required for optimal phosphorylation of Cbl-b in response to activation of the Met receptor and for optimal ubiquitination of the Met receptor by Cbl-b. This provides insight into the mechanism of action of the Cbl-b protein. We have continued to study the induction of apoptosis by TRAIL in breast cancer cells. We have shown that inhibitors of the EGFR can enhance TRAIL-mediated apoptosis in breast cancer cells which express EGFR. Interestingly, it appears that the subset of breast cancer cells which do not express estrogen receptor or ErbB-2 are most affected by EGFR inhibition. These estrogen receptor and ErbB-2 negative tumors have a poor prognosis and can only be treated with chemotherapy. Our data raise the possibility of using molecularly targeted therapy (e.g., the combination of EGFR inhibitors and TRAIL) for the treatment of these tumors.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Intramural Research (Z01)
Project #
1Z01SC007263-15
Application #
7594781
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
15
Fiscal Year
2007
Total Cost
$1,314,511
Indirect Cost
Name
National Cancer Institute Division of Clinical Sciences
Department
Type
DUNS #
City
State
Country
United States
Zip Code
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Davies, Gareth C; Ettenberg, Seth A; Coats, Ashley O et al. (2004) Cbl-b interacts with ubiquitinated proteins; differential functions of the UBA domains of c-Cbl and Cbl-b. Oncogene 23:7104-15

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