Showing Latest Articles
Coactivation of receptor tyrosine kinases in malignant mesothelioma as a rationale for combination targeted therapy
Journal of Thoracic Oncology, 09/02/2011
Clinical Article
Brevet M et al. – Combination targeting of kinase signaling pathways is more effective than single agents in most MM.
Methods- Performed a screen for mutated or activated RTKs in 14 MM cell lines and 70 primary tumors
- Expression of phosphorylated RTKs was analyzed by Western blotting and a membrane-based antibody array in normal growth conditions and after treatment by specific inhibitors
- MET and epidermal growth factor receptor (EGFR) mutations were screened by sequencing
- MET, hepatocyte growth factor, insulin-like growth factor 1 receptor, and EGFR expression were studied by Western blotting, immunohistochemistry, enzyme-linked immunosorbent assay, and by Affymetrix expression microarrays
- Profiling of phosphorylation status of 42 RTKs showed prominent coactivation of MET and EGFR in 8 of 14 (57%) MM cell lines
- MET, EGFR, and insulin-like growth factor 1 receptor were main RTKs activated after mTOR inhibition and contributed to AKT feedback activation
- Knockdown of MET by RNA interference inhibited not only the phosphorylation of MET but also that of EGFR
- Stimulation with hepatocyte growth factor increased both phospho-MET and phospho-EGFR
- The combination of PHA-665752 and the EGFR inhibitor, erlotinib, suppressed cell growth more than either agent alone in three of 6 cell lines tested
- Combinations of rapamycin and different RTK inhibitors were more active than either drug alone in 12 of 13 cell lines
