N pERK1 / 2 is a good biomarker, recent reports have shown that pERK level is actually a poor indicator of the RAF or RAS mutation status BN, and not a good marker for a slower growth compared to the levels of Ki67. In addition, a recent study showed that the inhibition of ERK kinase inhibitors of AP23573 RAF RAF B hangs Mutation status. Therefore, it is important to spread PUBLIC known mutational status of RAF B before the evaluation of the effectiveness of pharmacological agents and tumor progression. Currently targeting ERK or B-RAF or MEK1 / 2 inhibits effectively reduced phosphorylated ERK1 / 2 levels, but tumors with wild-type RAF showed increased Hte concentration of pERK w During treatment with PLX4032. In these Cases k Nnte targeting an inhibitor of ERK as SPRY2 be a better option for melanoma-containing wild-type BRAF.
SiRNA-mediated knockdown SPRY2 reduced ERK in melanocytes in melanoma cells with Luteolin wild-type B-RAF, but not those with V600EB RAF. SPRY2 and SPRY4 directly bind wild-type but not mutant B RAF RAF B suggesting that the loss of the SPRY could improve levels of active ERK, so that the growth of melanoma cells with wild-type B-RAF. Treatment of melanoma cells with the RAF inhibitor AZ628 B led to the development of clones with high Perk, the place due to the activation of RAF C leads to further proliferation in the presence of the drug has. Therefore k Nnte Combination with RAF B MEK1 / 2 and / or C-RAF inhibitors the most effective approach to ERK his goal. Some melanomas with mutations RAFV600E B can intrinsically resistant to inhibitors of RAF B following amplification of cyclin D1.
Thus there is a need to develop specific small molecule inhibitors of the ERK 1/2. 3.0. Targeting other tracks in combination with inhibition of the MAPK pathway V600EB Although RAF is the key to developing melanoma, pharmacological agents inhibit members of the MAP kinase cascade signaling lacks efficacy or cells rapidly develop resistance to them. Sorafenib, U0126, PD98059 or ineffective. As monotherapy for the treatment of patients with advanced melanoma Therefore, it is reasonable to assume that the signaling proteins must, m May receive for the inhibition of melanoma are better targeted. This M Possibility is supported in studies with siRNA, inhibition and AKT3 V600EB RAF, both proteins Showed simultaneously targeting synergistically inhibited tumor growth of melanoma cells in culture and in xenograft.
Likewise, CO combination nanoliposomes ceramide with sorafenib with MEK inhibitors U0126, PD325901 and PD98059 or more effectively reduce mTORC1 melanoma cell growth in terms of each of these individual agents treated. In another study, topical application of LY 294002 and U0126 in combination effective in reducing the incidence of malignant melanoma and Tumorwachstumsverz Delay. Moreover, inhibitors of PI3K and MEK are only effective when used in combination. MEK inhibitors have shown that the growth of melanoma cells by inducing cell cycle arrest, and upregulation of p27 block in cultures, but were rapidly reversible after washing inhibitor. However, if the PI3 kinase inhibitors, and MEK were combined, the growth and invasion of metastatic melanoma locked. Thus aggressive melanomas are