Activation of FOXO3a Is Sufficient to Reverse Mitogen-Activated Protein/Extracellular Signal-Regulated Kinase Kinase Inhibitor Chemoresistance in Human Cancer

作者：Yang, Jer-Yen; Chang, Chun-Ju; Xia, Weiya; Wang, Yan; Wong, Kwok-Kin; Engelman, Jeffrey A.; Du, Yi; Andreeff, Michael; Hortobagyi, Gabriel N.; Hung, Mien-Chie^*

来源：Cancer Research, 2010, 70(11): 4709-4718.

DOI：10.1158/0008-5472.CAN-09-4524

• TRANSCRIPTION FACTORS
• IN-VIVO
• PROMOTES TUMORIGENESIS
• AZD6244 ARRY-142886
• ANTITUMOR-ACTIVITY
• MEK INHIBITION
• CELL-LINES
• AKT
• PATHWAY
• MODELS

Drug resistance is a central challenge of cancer therapy that ultimately leads to treatment failure. In this study, we characterized a mechanism of drug resistance that arises to AZD6244, an established mitogen-activated protein/extracellular signal-regulated kinase kinase (MEK) 1/2 inhibitor currently being evaluated in cancer clinical trials. AZD6244 enhanced the expression of transcription factor FOXO3a, which suppressed cancer cell proliferation. In AZD6244-resistant cancer cells, we observed the impaired nuclear localization of FOXO3a, reduced FOXO3a-mediated transcriptional activity, and decreased the expression of FOXO3a target gene Bim after cell treatment with AZD6244. Resistant cells could be sensitized by phosphoinositide 3-kinase (PI3K)/AKT inhibitors, which are known to enhance FOXO3a nuclear translocation. Our findings define FOXO3a as candidate marker to predict the clinical efficacy of AZD6244. Furthermore, they suggest a mechanism of resistance to MEK inhibitors that may arise in the clinic yet can be overcome by cotreatment with PI3K/AKT inhibitors. Cancer Res; 70(11); 4709-18.

• 出版日期2010-6-1
• 单位中国医科大学