As shown in Figure 5A, evaluating the individual com bination index for all combinations tested revealed that E6201 and selleck catalog LY294002 exhibit synergistic Inhibitors,Modulators,Libraries activity in all six melanoma cell lines, irrespective of E6201 sensitivity or PTEN or pAkt status. Interestingly, different patterns of synergy were observed among the groups of cell lines tested. While most of the cell lines showed an in creasing combination index at higher concentrations of E6201, UACC647 and UACC558 cells showed a decreasing combination index or enhanced synergy with increasing concentrations of E6201. Notably, this pattern observed for UACC647 and UACC558 cells occurs within the context of high pAkt and relative resistance to E6201, supporting the hypoth esis that administration of a PI3K inhibitor can sensitize E6201 resistant cells with high pAkt levels to E6201.

In summary, the combination of E6201 and LY294002 resulted in synergistic activity in Inhibitors,Modulators,Libraries all six melanoma cell lines tested, as defined by a combination index 1. Inter estingly, enhanced synergy of E6201 with LY294002 treatment in the E6201 resistant cell lines UACC647 and UACC558 was observed at high concentrations of E6201. Discussion E6201 is a novel MEK1/2 inhibitor which inhibits selected cancer specific kinases that is currently in clin ical trials for solid tumours and, as a result of the data presented herein, is undergoing Phase I expansion in BRAF mutant malignancies. In the current study, we established a diverse cell line panel to not only represent the known genetic heterogeneity in melanoma, but also to enrich for rare mutations or genotypes in which to test the effectiveness of E6201 in vitro and in vivo.

From this genetically di verse panel, we demonstrate for the first time Inhibitors,Modulators,Libraries that sensi tivity to MEK1/2 inhibition in vitro correlated with wildtype PTEN suggesting parallel signalling of the PI3K/Akt/mTOR pathway may play a role in the resist ance of melanoma cell lines to E6201 and MEK1/2 inhi bitors in general. To this end we demonstrate that concurrent Inhibitors,Modulators,Libraries targeting of the Ras/Raf/MAPK and the PI3K/Akt/mTOR pathways was more effective than tar geting either of the pathways alone in all six cell lines studied with the Inhibitors,Modulators,Libraries greatest synergy observed in E6201 re sistant cell lines. These results underscore the power of heterogeneous cell line panels, such as the NCI60, to identify potential biomarkers of sensitivity and resistance in a clinical setting.

There is a general consensus that genomic analysis of tumours through The Cancer Genome Atlas and the www.selleckchem.com/products/Cisplatin.html International Cancer Genome Consortium will identify the core pathways activated in each tumour. Previous work in pancreatic cancer indicates that only 12 pathways need to be activated. This has been interpreted as molecular targeting of only a few pathways may be needed to effectively treat cancer. Emerging N Ras/BRAF/ERK data would suggest that some therapies will only work on pathways activated at a certain node.