Activation of FOXO3a is Sufficient to Reverse Mitogen-activated Protein/extracellular Signal-regulated Kinase Kinase Inhibitor Chemoresistance in Human Cancer

Overview

Journal Cancer Res

Specialty Oncology

Date 2010 May 21

PMID 20484037

Citations 42

Authors

Jer-Yen Yang

Chun-Ju Chang

Weiya Xia

Yan Wang

Kwok-Kin Wong

Jeffrey A Engelman

Yi Du

Michael Andreeff

Gabriel N Hortobagyi

Mien-Chie Hung

Affiliations

Soon will be listed here.

Abstract

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.

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