Fifth, and ATP-competitive MAP / ERK kinase 1/2 egfr review kinase MEK inhibitor target this critical RAS / ERK. A clinical Phase I AZD6244 has shown promising results in solid tumors with the best clinical response in many cancer patients heavily pretreated. AZD6244 Phase II clinical trials in various cancers including breast, lung, colon, liver, pancreatic, melanoma, and are either under way or recently completed. FOXO3a, a transcription factor FOXO family, is a tumor suppressor crucial. FOXOs in various types of tumors, including breast, prostate, glioblastoma, rhabdomyosarcoma, and leukemia Chemistry deregulated. Activated as a transcription factor, or suppress FOXOs several target genes, such as p27kip1 and cyclin D cell cycle regulation and Bim and FasL to induce apoptosis.
The loss of FoxO1a by chromosomal deletion has been shown that prostate cancer androgenunabh Ngigen to pr Sentieren. Moreover, the cytoplasmic localization or decrease was FOXOs of AKT, IKK, and ERK-mediated phosphorylation observed in breast cancer. The inhibition of the expression and activity of t FOXO3a is important rdern the cellular f Re transformation, tumor progression and angiogenesis. Therefore, FOXO family members have been proposed, important factors that influence the effectiveness of a variety of chemotherapeutic agents. For example, chemotherapy drugs paclitaxel and Akt / protein kinase B signaling inhibitor-2 / TRICIRIBINE used clinically for the treatment of breast cancer and myeloid leukemia Chemistry Acute, FOXO3a by AKT activity to enable t.
Based on our previous findings of down-regulation of FOXO3a by ERK, we were curious to inquire, whether mediated FOXO3a is a crucial target for AZD6244 cell cycle and apoptosis. In fact, we found that AZD6244 G1 growth and apoptosis of cells verst RKT through downregulation of ERK phosphorylation and stabilization of FOXO3a in AZD6244-treated mice cancer cell lines and xenograft tumors in M. In addition, FOXO3a and Bim flap behind apoptotic gene defect AZD6244-induced growth suppression, suggesting that FOXO3a and Bim are key objectives of AZD6244. In addition, cancer cells resistant to reduced nucleic AZD6244 showed impaired Re translocation of endogenous FOXO3a and Bim activation. LY294002 and API 2, AZD6244 by the restoration of FOXO3a nuclear translocation and activation of Bim, in synergy with AZD6244 in proliferation and suppression of colony formation in the resistant cells.
Development of resistance of cancer cells in cancer therapy is a clinically significant problem, so it is important to understand the molecular mechanisms that drugs contribute to drug resistance to understand and better identify the molecular targets for new therapies to overcome those resistance. Previous reports have suggested that cancer cells resistant to inhibitors of MEK, the activation of phosphoinositide 3-kinase / AKT signaling have. These data are consistent with our results showing that AZD6244 FOXO3a in resistant cells, which is probably inactivated in the activation of Akt. Our data show that the combination of AZD6244 treatment with pharmacological agents that FOXO3a activity to f t Rdern AZD6244 effectively treat resistant cells FOXO3a activation by modulation and related