Targeting AKT/mTOR and ERK MAPK signaling inhibits hormone-refractory prostate cancer in a preclinical mouse model.
Kinkade, Carolyn Waugh 1; Castillo-Martin, Mireia 2,3; Puzio-Kuter, Anna 1,3; Yan, Jun 1,3; Foster, Thomas H. 4; Gao, Hui 5; Sun, Yvonne 5; Ouyang, Xuesong 5; Gerald, William L. 6,7; Cordon-Cardo, Carlos 1,2,3; Abate-Shen, Cory 1,2,3,5
[Article]
Journal of Clinical Investigation.
118(9):3051-3064, September 2008.
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The AKT/mammalian target of rapamycin (AKT/mTOR) and ERK MAPK signaling pathways have been shown to cooperate in prostate cancer progression and the transition to androgen-independent disease. We have now tested the effects of combinatorial inhibition of these pathways on prostate tumorigenicity by performing preclinical studies using a genetically engineered mouse model of prostate cancer. We report here that combination therapy using rapamycin, an inhibitor of mTOR, and PD0325901, an inhibitor of MAPK kinase 1 (MEK; the kinase directly upstream of ERK), inhibited cell growth in cultured prostate cancer cell lines and tumor growth particularly for androgen-independent prostate tumors in the mouse model. We further showed that such inhibition leads to inhibition of proliferation and upregulated expression of the apoptotic regulator Bcl-2-interacting mediator of cell death (Bim). Furthermore, analyses of human prostate cancer tissue microarrays demonstrated that AKT/mTOR and ERK MAPK signaling pathways are often coordinately deregulated during prostate cancer progression in humans. We therefore propose that combination therapy targeting AKT/mTOR and ERK MAPK signaling pathways may be an effective treatment for patients with advanced prostate cancer, in particular those with hormone-refractory disease.
Copyright (C) 2008 The American Society for Clinical Investigation, Inc.