Clinical and molecular evidences of epithelial to mesenchymal transition in acquired resistance to XXXX -TKIs.

@entity1 @entity4562 @entity470 @entity5 @entity2 @entity669 @entity9513 @entity3866
BACKGROUND: Epithelial-to-mesenchymal transition (EMT), which was related with an acquired resistance to @entity4562 , was found in the @entity2 cell line. However, the clinical feasibility of this finding is still questionable. Here, we investigated whether EMT could be detected in a more clinically suitable situation using @entity1 's @entity5 and cells with deletion mutation on exon 19 of @entity470 gene. METHODS: @entity1 cell line was used to establish the subline resistant to @entity470 -TKIs. The induction of EMT was analyzed by immunostainings and Western blots in resistant cells and biopsied tissue from a @entity1 with acquired resistance to @entity3866 . Migration and invasion assay was performed to characterize the resistant cells. EMT-related genes expression was evaluated by cDNA microarray. Phospho-receptor @entity669 kinase array analysis was carried out to find bypass activating signals such as MET. RESULTS: We found that EMT developed in a @entity2 @entity1 who had an acquired resistance to @entity3866 while there were no known resistant mechanisms such as @entity9513 and MET amplification. CL-387,785-resistant cells (HCC827/CLR) were obtained by long-term exposure to increasing concentrations of CL-387,785 (an irreversible @entity470 -TKI). The morphological and molecular maker changes compatible with EMT were also found in @entity1 /CLR cells. However, there were also no secondary @entity9513 mutation and MET amplification. Furthermore, the activity of most of tested RTKs including receptor HER family was decreased suggesting that there was no bypass activating signal leading to resistance. These cells showed an enhanced capability for migration (   1.6-fold) and invasion (   2.8-fold). CONCLUSION: EMT should be considered as one of possible mechanisms for the acquired resistance to @entity470 -TKIs in @entity2 cells.
