The molecular basis for this relative high frequency of natural resistance of BRAFV600E mutant cutaneous melanoma cell lines in Dorsomorphin order our series is currently not well understood. Initial exploration of secondary oncogenic events in the PI3K/AKT pathway did not clearly differentiate naturally sensitive and resist ant BRAFV600E mutant cutaneous melanomas to the BRAF inhibitor vemurafenib, but downstream signaling studies did suggest that the PI3K/AKT pathway may be involved. In the current studies we noted the same phenomenon, a lack of correlation between natural sensitivity and resistance to TAK733 based solely on oncogenic analysis of the cell lines using SNP arrays or targeted oncogene sequencing for mutations frequently present in cancer.

However, there was a suggestion from Western blot analyses of signaling pathways that differ ential effects of MEK inhibitor Inhibitors,Modulators,Libraries altering signaling Inhibitors,Modulators,Libraries through the PI3K/AKT pathway may be related to resist ance. This observation may provide means to explore combinations of MEK inhibitors with PI3K or AKT inhi bitors that may be useful in NRAS or BRAF mutant mel anomas, which could be due to hyperactive receptor tyrosine kinase signaling leading to resistance. BRAF has only MEK as a substrate for activation, and as discussed cutaneous cell lines with the BRAFV600E mutation frequently have high sensitivity to MEK inhibitors in vitro. However, patients with BRAFV600E mutant Inhibitors,Modulators,Libraries cutaneous metastatic melan oma enrolled in clinical trials testing MEK inhibitors have lower response rates than the use of the type I BRAF inhibitors vemurafenib or dabrafenib in the same population.

The reason for this discrepancy Inhibitors,Modulators,Libraries between in vitro and in vivo results with MEK inhibitors is not clearly understood at this time, but it may be related to a lower therapeutic window of MEK inhibitors in the clinic compared to type I BRAF inhibitors. Inhibitors,Modulators,Libraries This could be explained by the paradoxical activation of the MAPK pathway in BRAF wild type cutaneous cells, where type I BRAF inhibitors increase MAPK sig naling in normal cells, while they efficiently block the MAPK pathway downstream of oncogenic GW-572016 BRAFV600. On the contrary, MEK inhibitors can equally block the MAPK pathway downstream of both oncogenic and wild type BRAF. This lack of differentiation most likely causes the dose limiting toxicities at exposures in vivo that do not adequately block the MAPK pathway in BRAFV600 mutant melanoma. Despite this, MEK inhibitors are likely to have a role in the treatment of cancers with constitutive MAPK signaling from onco genic mutations upstream of MEK.