Experimental studies on ErbB targeted therapy in malignant melanoma

摘要: Background: Acquired resistance to cancer therapy, including targeted therapies such as epidermal growth factor receptor (ErbB) tyrosine kinase inhibitors (TKIs), constitutes a major clinical problem in treating patients with malignant disease. Several drug mechanisms for ErbB1 TKIs involving abnormal activation of receptors or intracellular signaling pathways have been discovered. ErbB recently shown inhibit melanoma cells. This study was undertaken develop gefitinib-resistant cell line order find any mechanism gefitinib cells lacking activating mutation BRAF NRAS.Material and methods: A (RaH5) made resistant the TKI by continuous culture stepwise increasing concentrations up 10 μM. The phosphorylation status 42 different human kinases screened protein array (RaH5ZDR) wild-type RaH5 treated without gefitinib. PI3K, MAPK Stat3 were studied an analogous way Western blot analysis; 2-D gel electrophoresis performed determine other potential proteins involved In addition, effect pan-ErbB canertinib on investigated.Results: Protein experiments showed that only Met insulin (IR) exhibited substantially increased RaH5ZDR compared their nonresistant counterparts. Interestingly, following treatment ErbB2 ErbB3 equally well suppressed non-resistant However, downstream Akt Erk1/2 inhibited greater extent cells.Conclusion: Resistance appears be related expression IR linked more persistent through Erk1/2. additional studies are required further elucidate our experimental system.