EGFR/Met association regulates EGFR TKI resistance in breast cancer
Open Access
- 12 July 2010
- journal article
- Published by Journal of Molecular Signaling in Journal of Molecular Signaling
- Vol. 5 (1), 8
- https://doi.org/10.1186/1750-2187-5-8
Abstract
Breast cancers show a lack of response to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs), despite 30% of tumors expressing EGFR. The mechanism of this resistance is unknown; however, we have recently shown that Met kinase activity compensates for loss of EGFR kinase activity in cell culture models. Met has been implicated in the pathogenesis of breast tumors and therefore may cooperate with EGFR for tumor growth. Here we have found that EGFR phosphorylation and cell proliferation is in part regulated by Met expression. In addition, we found that Met constitutive phosphorylation occurred independent of the Met ligand hepatocyte growth factor (HGF). Ligand-independent Met phosphorylation is mediated by Met amplification, mutation, or overexpression and by Met interaction with other cell surface molecules. In SUM229 breast cancer cells, we found that Met was not amplified or mutated, however it was overexpressed. Met overexpression did not directly correlate with ligand-independent Met phosphorylation as the SUM229 cell line was the only Met expressing breast cancer line with constitutive Met phosphorylation. Interestingly, Met expression did correlate with EGFR expression and we identified an EGFR/Met complex via co-immunoprecipitation. However, we only observed Met constitutive phosphorylation when c-Src also was part of this complex. Ligand-independent phosphorylation of Met was decreased by down regulating EGFR expression or by inhibiting c-Src kinase activity. Lastly, inhibiting EGFR and Met kinase activities resulted in a synergistic decrease in cell proliferation, supporting the idea that EGFR and Met functionally, as well as physically interact in breast cancer cells to regulate response to EGFR inhibitors.Keywords
This publication has 37 references indexed in Scilit:
- Met and c-Src Cooperate to Compensate for Loss of Epidermal Growth Factor Receptor Kinase Activity in Breast Cancer CellsCancer Research, 2008
- Showering c-MET-dependent cancers with drugsCurrent Opinion in Genetics & Development, 2008
- From Tpr-Met to Met, tumorigenesis and tubesOncogene, 2007
- Novel D761Y and Common Secondary T790M Mutations in Epidermal Growth Factor Receptor–Mutant Lung Adenocarcinomas with Acquired Resistance to Kinase InhibitorsClinical Cancer Research, 2006
- Genomic organization of the 8p11∼p12 amplicon in three breast cancer cell linesCancer Genetics and Cytogenetics, 2004
- Integral Role of the EGF Receptor in HGF-Mediated Hepatocyte ProliferationBiochemical and Biophysical Research Communications, 2002
- Expression of the C-Met/HGF receptor in human breast carcinoma: Correlation with tumor progressionInternational Journal of Cancer, 1997
- Germline and somatic mutations in the tyrosine kinase domain of the MET proto-oncogene in papillary renal carcinomasNature Genetics, 1997
- Hepatocyte growth factor/scatter factor expression in human mammary epithelium.1994
- Epidermal growth factor receptor expression as a prognostic indicator in breast cancerEuropean Journal of Cancer and Clinical Oncology, 1991