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- W2605256583 abstract "The combination of dabrafenib and trametinib is a targeted therapy for BRAF-mutated metastatic melanoma. Although this combination therapy has proven clinical benefits in cutaneous melanoma, some patients still develop resistance. However, the mechanism of the drug resistance is largely unknown. In this study, we established A375 drug resistant clones (A375DR, A375TR, and A375DTR cells) by chronically exposing A375 cells to dabrafenib and/or trametinib, and further confirmed the drug resistance by Western Blot and MTT assay. Besides, we found the downstream target(s) in drug resistance by microarray, recombinant protein, antagonists and RNA interference knockdown system. We also established A375 resistant tumors by oral gavage of dabrafenib and trametinib every day in a nude mice xenograft model. When the mice developed relapsed tumors after initial regression, we collected tumor and blood samples for further real-time RT-PCR, ELISA and immunohistochemistry studies. We found that endothelin-1 (ET-1) was increased in A375 drug resistance clones, especially A375DTR cells, and the drug resistance ability were decreased by ET-1 shRNA knockdown. Phosphorylation of Akt was increased through ET-1-ETBR signalling pathway in A375DTR cells. Furthermore, inhibition of Akt phosphorylation or blockade of ETBR reversed the drug resistance ability of A375DTR cells. In conclusion, we demonstrated the molecular mechanism of acquired resistance to dabrafenib and trametinib cotreatment in cutaneous melanoma involves ET-1 and Akt activation. ET-1 may be a potential therapeutic target for acquired resistance to dabrafenib and trametinib co-treatment in cutaneous melanoma." @default.
- W2605256583 created "2017-04-14" @default.
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- W2605256583 date "2017-05-01" @default.
- W2605256583 modified "2023-09-25" @default.
- W2605256583 title "Acquired resistance to dabrafenib and trametinib cotreatment in cutaneous melanoma involves endothelin1 (ET-1) and Akt activation" @default.
- W2605256583 doi "https://doi.org/10.1016/j.jdermsci.2017.02.244" @default.
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