3 years in patients wild type for both. Our cohort included 22 patients who received either dabrafenib, vemurafenib, a pan RAF inhibitor or a pan RAF inhibitor and vemurafenib. Patients with N RAS mutated mel anomas appear to have an increased rate of selleck chemical skin and soft tissue involvement compared to B RAF mutated counterparts and WT patients. The rate of lymph node metastasis was also noted to be higher in patients with N RAS muta tions compared to B RAF mutant and WT pa tients. No statistically significant difference was seen between the genotypes and other clinical characteristics, such as M stage and LDH levels. Seeing that B RAF inhibitors can affect survival in pa tients with B RAF mutant melanomas, this group of pa tients was removed from the survival analysis.
By Cox univariate analysis we found a trend towards shorter sur vival in the N RAS mutant population, compared to the B RAF and WT groups Inhibitors,Modulators,Libraries combined. The median survival was 13 and 19. 6 months, respectively. Kaplan Meier survival curves Inhibitors,Modulators,Libraries are shown in Figure 1a for the three groups of patients and Figure 1b for the two groups to visually demonstrate the differences between the groups. Interestingly, analysis of anatomic sites at the time of initial diagnosis of stage IV disease revealed a higher rate of brain involvement among B RAF and N RAS mutant melanoma patients, compared with pa tients with WT disease. With longitu dinal follow up, however, the rate of development of brain metastases did not differ among the Inhibitors,Modulators,Libraries three groups, possibly because the WT groups lived longer and thus developed brain metastases over time.
In vitro activity of B RAF and MEK inhibitors in a large panel of melanoma cultures To investigate the effect of Inhibitors,Modulators,Libraries B RAF and MEK inhibition in melanoma cultures, we used RAF265, MEK162 and the MEK in hibitor trametinib. A panel of 22 patient derived melanoma cultures was used. the IC50 for RAF265 and MEK162 are shown in Table 2. This was compared to the IC50 for trametinib. Cells were treated with each drug individually at con centrations ranging from 1 nM to 1000 nM and ana lyzed three days later. As shown in Table 2, the IC50 for RAF265 ranged from 24 to 10000 nM, 4 to 2004 nM, and 62 to 2082 nM for WT, Inhibitors,Modulators,Libraries B RAF mutant and N RAS mutant cultures, respectively. The IC50 for MEK162 ranged from 10 to 10000 nM, 1 to 150 nM, and 4 to 13 nM for WT, B RAF mutant and N RAS mutant mel anoma cultures, respectively.
The sensitivity to RAF265 in wild type and N RAS melanoma cultures was low. Two wild type cultures are sensitive to both RAF265 and MEK162. Six of ten B RAF mutant cultures were sensitive to RAF265, and seven out of ten were sensitive to MEK162. In N RAS mutant melanoma cultures, 2 out of 7 were sensitive to RAF265 and, strik ingly, all were sensitive to MEK162. Of the ARQ197 7 N RAS mutant cultures, 5 were sensitive to trametinib. YUFIC and YUTICA were more resistant.
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