Moreover, inhibition of AKT activity leads to potent dephosphorylation of known

The sensitivity profile is thereby in the same range compared to the additionally tested dual PI3K MTOR inhibitor, NVP BEZ235. It was previously noted, that the キナーゼ 阻害剤 predominant antitumor effect of inhibitors of PI3K AKT MTOR signaling cascades is mediated via inhibition of cellular proliferation rather than induction of apoptosis. Surprisingly how ever, NVP BGT226 proved to have genuine proapoptotic efficacy whilst the proapoptotic effect achieved by NVP BEZ235 was, as expected by previous reports, at most moderate. To model the effects of NVP BGT226 and NVP BEZ235 on mutant TK triggered AKT activation, we chose two well established acute leukemia cell lines harboring a FLT3 ITD mutation or a BCR ABL1 mutation. Similar to the findings for Jurkat cells, both inhibitors, proved to be highly potent in inhibiting cellular proli feration.<br><br> However again, NVP BEZ235 オーダー Lenalidomide only moderately induced a meaningful proapoptotic effect, whereas NVP BGT226 was a strong inducer of the programmed cell death machinery. As the AKT pathway controls cell cycle checkpoints, we speculated that the discrepancy may be due to differential activity on the cell cycle compartment. And indeed, a strong and sustained G0 G1 arrest was observed for NVP BEZ235 preventing cells to undergo apoptosis. On the protein level, where both agents were similarly targeting downstream proteins controlling cell cycle pro gression or ULK1 induced autophagy, only NVP BGT226 was capable to override cell protective mechanisms to potently induce apoptosis.<br><br> We speculated that the cell cycle arrest induced by NVP BEZ235 might be overcome by combination ap proaches: TKI, for which we demonstrated insufficient global suppression of AKT signaling pathways but additional effects on alternative survival pathways such as MAPK and STAT signaling, may be an attractive mo lecularly defined partner to combine with dual PI3K MTOR inhibitors. LY2603618 Checkpoint 阻害剤 Indeed on the protein level, combin ation of TKI with either of the tested dual PI3K AKT in hibitors efficiently and globally shut down AKT signaling pathways as well as additional targets triggered by mutant TKs. In an attempt to mathematically define the extend of combination efficacy, we established isobologram assays to compute combination indices. Together, calculated CIs for TKI plus dual PI3K MTOR inhibitor treatment were close to or smaller than 1, indicating an additive to superadditive effect for all tested endpoints.<br><br> Notably, combination of TKI with NVP BEZ235 was capable to override cell cycle arrest seen for NVP BEZ235 monotherapy to potently induce apoptosis in leukemia cells. One might speculate that cell type specific off target effects may have prevented cells to undergo apoptosis. To confirm our findings, we established an isogenic Ba F3 cell line model transfected with FLT3 ITD or BCR ABL1 mutations. NVP BGT226 revealed high potency to inhibit cellular proliferation in the same range as NVP BEZ235. As expected, while meaningful proapoptotic effects were achieved by NVP BGT226 in all cell strains, FLT3 ITD and BCR ABL1 transfected Ba F3 cells were only moderately sensitive towards NVP BEZ235.