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Transcriptional changes associated with melanoma resistance to small inhibitor treatment
Dorčáková, Terézia ; Kolář, Michal (advisor) ; Modrák, Martin (referee)
Malignant melanoma is an aggressive skin tumour with increasing incidence and, in advanced stages, limited therapeutic results. The major oncogenic alteration in melanoma is mutational activation of the B-Raf protein, with the predominant mutation V600E, which occurs in 60% of cases and hyperactivates the ERK signaling pathway. This cascade of Raf, MEK and ERK protein kinases is an integral part of an evolu- tionarily conserved signaling network that allows eukaryotic cells to sense a variety of extracellular signals. These protein kinases sequentially activate each other and translate extracellular signals into cellular responses such as proliferation, di↵erentiation, cell cycle changes, apoptosis or cell migration. The central role of the ERK pathway in oncogen- esis has made it one of the targets for therapeutic intervention, and inhibitors targeting mutant Raf, such as vemurafenib or dabrafenib, have been approved for the treatment of melanoma. These molecules specifically target B-Raf(V600E) and have led to a revo- lution in melanoma treatment. Unfortunately, such targeted therapy is complicated by the ability of cancer cells to acquire resistance. The aim of this work is to study at the transcriptional level the emergence of this resistance in patients who respond well to treatment and in...
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