Journal
ONCOGENE
Volume 31, Issue 30, Pages 3505-3515Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/onc.2011.518
Keywords
cancer therapy; EGF; growth factor; tyrosine kinase; signal transduction
Funding
- National Cancer Institute [CA072981]
- Israel Cancer Research Fund
- Dr Miriam and Sheldon G Adelson Medical Research Foundation
- Linda and Michael Jacobs Charitable Trust
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Epidermal growth factor (EGF)-like growth factors control tumor progression as well as evasion from the toxic effects of chemotherapy. Accordingly, antibodies targeting the cognate receptors, such as EGFR/ErbB-1 and the co-receptor HER2/ErbB-2, are widely used to treat cancer patients, but agents that target the EGF-like growth factors are not available. To circumvent the existence of 11 distinct ErbB ligands, we constructed a soluble fusion protein (hereinafter: TRAP-Fc) comprising truncated extracellular domains of EGFR/ErbB-1 and ErbB-4. The recombinant TRAP-Fc retained high-affinity ligand binding to EGF-like growth factors and partially inhibited growth of a variety of cultured tumor cells. Consistently, TRAP-Fc displayed an inhibitory effect in xenograft models of human cancer, as well as synergy with chemotherapy. Additionally, TRAP-Fc inhibited invasive growth of mammary tumor cells and reduced their metastatic seeding in the lungs of animals. Taken together, the activities displayed by TRAP-Fc reinforce critical roles of EGF-like growth factors in tumor progression, and they warrant further tests of TRAP-Fc in preclinical models. Oncogene (2012) 31, 3505-3515; doi:10.1038/onc.2011.518; published online 21 November 2011
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