For example, the treatment of human melanoma cell line C8161 with MEK1 inhibitor PD98059 sensitized cells to apoptosis by cisplatin induced. In three other melanoma cell lines, has not PD98059 foreign Sen apoptosis induced by cisplatin, and in a cell Dihydromyricetin line, the cells are protected. Therefore, MEK1 / 2 block abh-Dependent cell line and can not be considered as a general approach to inhibit melanoma tumor growth or to sensitize cells to chemotherapeutic agents. Although the mechanism leading to resistance to inhibitors of MEK1 / 2 remains uncertain, a final result of resistant clones from a random generated MEK1 screen as astumors of patients obtained after treatment with relapsed allosteric MEK inhibitor AZD6244.
Mutations have been identified that confer resistance to inhibitors by interrupting the allosteric binding site of drugs or alpha helix C, which leads to an increase of 100 times LY2157299 the resistance to MEK inhibition MEK. Mutations in MEK1 and P124L Q56P have also been identified in patients treated with the MEK inhibitor AZD6244. These mutations affected MEK1 codons within or in the N eh The N-terminal helix A and is negative regulatory transmitted resistance PLX4720. Cells were treated with AZD6244 patients showed disease stabilization transient that was followed by a relapse and then Treatment with PLX4720. AZD6244 resistant melanoma cells were resistant to PLX4720, a value of 10 M compared GI50 5 10 nM in cells pretreated ?. Developed mechanical strength. Mutations in MEK P124L and P124S mutations conferred resistance two to three times more in comparison with wild-type MEK1, w While mutations conferred resistance Q56P PLX4720 robust 50-fold, compared with the MEK allele.
Mirror after PLX4720 treatment pMEK showed comparable reduction of all MEK1 resistance alleles strongly suggests that clinically relevant MEK1 resistance mutations confer k Can cross-resistance to RAF inhibition as prevention of resistance mediated by MEK will likely require targeting multiple points of MAPK. Simultaneously exposing melanoma cells with mutant B AZD6244 and PLX4720 for RAF prevented the emergence of resistant clones, suggesting the potential for multiple points in this signaling cascade th goal to melanoma cells to t To prevent the development of resistance, this k Nnte important clinical implications.
Therefore, k Nnte the combined inhibition of MEK and RAF acquired resistance to targeted therapies for the MAP kinase pathway led deal. 4.3. The transition from B to C RAF RAF RAF C is generally not required for MEK and ERK signaling in melanoma cells when B RAF is mutated to a constitutively active form. But it is possible to change the passage in the RAF isoform occurs whether RAF or RAS B is mutated depends abh. Is mutated in melanocytes or melanoma with BRAF, is RAF B Haupt Chlich responsible for the signaling of MEK and ERK. However, when RAS is mutated, cells move RAF C. If cAMP signaling was blocked, dephosphorylated to S43 and S233 of the RAF B and conditions that enable the de-differentiation of melanocytes, a transition from B to C RAF RAF activation of growth factors. Agents, to activate the cAMP production not block the proliferation of melanocytes e