AlthoughPI3K downstream targets and pS70S6K pact. Although treatment with rapamycin kicked Born erh FITTINGS pAkt compared to untreated cells, treatment with LY294002 both alone and in combination with rapamycin to a downregulation of pAkt and as shown in Figure 2A pP70S6K. We notice there the degree of reduction of pAkt pP70S6K and equal to or better with the lowest concentration LY317615 of rapamycin in comparison to h Heren concentrations. Given the poor pharmacological properties of LY294002, we then studied the synergy between PI3K inhibitor from Novartis clinical quality t, NVP BKM120 and rapamycin developed. The IC50 for the panel of five cell lines for BKM120 NVP alone ranged from 1.06 to 2.28 m. Synergy in all five cell lines was observed at lower concentrations of NVP BKM120, as shown in Table 1, and the h HIGHEST concentration remained YUSIK YULAC and synergistic.
YUKSI and YUVON were additive ENMD-2076 with 1 M rapamycin, but in synergy with h Heren concentrations. Yucas remained in synergy with NVP BKM120 in 1000 M, but 1 to 100 M rapamycin antagonists. As shown in Figure 2B, was the combination of rapamycin and LY294002 and NVP BKM120 and all concentrations of rapamycin Born a decrease in Lebensf Ability of cells using comparable YULAC example. The activity of t One dual inhibitor of PI3K mTOR in melanoma cell lines, given the synergy between PI3K inhibitors and rapamycin observed in melanoma cell lines, we examined the activity of t an inhibitor dual PI3K mTOR is administered to patients with solid tumors in phase I clinical studies, NVP BEZ235.
To achieve broad activity t Test of PI3K mTOR inhibitor in melanoma cells double, we have expanded our panel of cell lines, a total of 23 cell lines harboring a Ras mutation N, 12 B harboring mutations eventually en Raf and 10 wild-type at a time . In 23 melanoma cell lines, the IC50 for NVP BEZ235 ranged from C M, as shown in Table 2. One of the proposed mechanisms for resistance mutations in the Ras Raf PI3KIs that in more than half of the H Of melanomas are found. By analysis of variance was no association between the IC50 of NVP BEZ235 and the presence or absence of Raf mutations found B. The objectives of the NVP BEZ235, pAkt and pP70S6K decreases both with the exposure to the drug in a manner dependent Ngig of the dose and the time, as shown in Figure 3B YUVON YUSIK and cell lines.
Compared to untreated cells, Pact, and an hour Greater degree pP70S6K 1 and 4 hours were downregulated and pAkt levels started hen increased after 4 hours of 100C M NVP BEZ235. Clonogenicity was examined in cells YUSIK YUVON and the exposure to the PI3K inhibitor mTOR doubles. As shown in Figure 3C, NVP BEZ235 effectively inhibits clonogenicity at low concentrations c M. The synergy between the two mTOR inhibitor NVP BEZ235 PI3K and MEK inhibitor AZD6244 in B Raf mutant and wild-type cell lines blocking mTOR is necessary strengths inhibition of PI3K to st, We finally studied efficacy of two PI3K mTOR