The mTORC1/2 Inhibitor AZD8055 Strengthens the Efficiency of the MEK Inhibitor Trametinib to Reduce the Mcl-1/[Bim and Puma] ratio and to Sensitize Ovarian Carcinoma Cells to ABT-737.

摘要: The identification of novel therapeutic strategies is an important urgent requirement for the clinical management ovarian cancer, which remains leading cause death from gynecologic cancer. Several studies have shown that antiapoptotic proteins Bcl-xL and Mcl-1, as well proapoptotic protein Bim, are key elements to be modulated kill cancer cells. Pharmacologic inhibition possible by using BH3-mimetic molecules like ABT-737. However, Mcl-1 and/or promotion its BH3-only partners (including Puma, Noxa) a challenge may achieved modulating signaling pathways upstream. This study sought whether AZD8055-induced mTOR trametinib-induced MEK could modulate decrease Mcl-1/BH3-only ratio thus sensitize various cell lines AZD8055 treatment inhibited increased Puma expression but did not induce massive apoptosis in combination with In contrast, trametinib, decreased upregulating dephosphorylated active sensitized IGROV1-R10 OVCAR3 cells Adding trametinib further reduced triggered without ABT-737 Moreover, AZD8055/trametinib association highly all including SKOV3 ABT-737, induced Bim being crucial this sensitization. Finally, three-drug was also very efficient when replacing pan-Akt inhibitor MK-2206. proposes original multitargeted implications design approaches treatment. Mol Cancer Ther; 16(1); 102-15. ©2016 AACR.