As such, the clinical outcome of future MEK1 2 trials may be improved selleckchem KPT-330 by identifying markers like BRAF to enrich the study with patients more likely to respond. As Ras is thought to provide resistance to BRAF and MEK inhibitors by activation of additional downstream pathways, MEK inhibitors might Inhibitors,Modulators,Libraries be best utilised in combination. Inter estingly, combined BRAF and MEK inhibition was recently shown to over come NRAS mediated resistance to BRAF inhibition in melanoma cells already harbouring BRAFV600 mutations. The combination therapy potently abrogated ERK signalling, inhibited cell growth and upregulated markers of apoptosis. Furthermore, this drug com bination was recently shown to induce tumour regression or stable disease in roughly two thirds of BRAFV600 mutant melanoma patients refractory to single agent BRAF inhibition.

As such, sequential targeting of the MAPK pathway at multiple nodes in BRAF mutant patients or targeting of parallel pathways, such as PI3K, in RAS mutant patients, may also improve the therapeutic response of melanoma patients to MEK1 2 inhibition. The aim of the current study Inhibitors,Modulators,Libraries was to utilize a diverse melanoma cell line panel of known mutational status to aid in the identification of a patient population most likely to respond to MEK inhib ition. We utilized E6201, a potent, novel inhibitor of MEK1 and MEK kinase 1 currently under devel opment as an anti cancer agent. E6201 is in a Phase I clinical trial for advanced solid malignancies that had an expansion phase to specifically include patients with BRAF mutant tumours. and outcome ana lysis is currently maturing.

Results Sensitivity to E6201 in a melanoma cell line Inhibitors,Modulators,Libraries panel Sensitivity to E6201 was assessed in a panel of 31 Inhibitors,Modulators,Libraries cell lines for which the mutation status of common mel anoma genes was known. These lines were chosen to represent different mutational profiles from a larger panel of more than one hundred melanoma cell lines. Western blots in Additional file 1 Figure S1 confirm that E6201 efficiently inhibits MEK1 2 ac tivity by virtue of its ability to abrogate phosphoryl ation of ERK1 2 in our entire panel of melanoma cell lines. The majority of the melanoma cell lines were sensitive to E6201. MAPK activation due to mutations in BRAF and NRAS was not significantly associated with increased sensitivity to E6201.

In the 26 cell Inhibitors,Modulators,Libraries lines carrying mutations in BRAF, NRAS, or HRAS, sensitivity to E6201 was statistically associated with wildtype PTEN status. Specific ally, of the 18 cell lines with wildtype PTEN, 17 were sensitive whereas in the 8 cell lines with mutant PTEN, only 4 were sensitive. Moreover, even if PTEN status alone is examined, E6201 sensitivity is associated, albeit non selleck chemicals Rapamycin significantly, with wildtype PTEN status. 23 31 cell lines are wildtype for PTEN and of these 20 are sensitive. Interestingly, 18 of the 24 sensitive cell lines also demonstrated hypersensitivity to E6201, with an IC50 100 nM.