Targeting AKT/mTOR and ERK MAPK signaling inhibits hormone-refractory prostate cancer in a preclinical mouse model
Carolyn Waugh Kinkade, … , Carlos Cordon-Cardo, Cory Abate-Shen
Carolyn Waugh Kinkade, … , Carlos Cordon-Cardo, Cory Abate-Shen
Published August 21, 2008
Citation Information: J Clin Invest. 2008;118(9):3051-3064. https://doi.org/10.1172/JCI34764.
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Research Article

Targeting AKT/mTOR and ERK MAPK signaling inhibits hormone-refractory prostate cancer in a preclinical mouse model

Abstract

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.

Authors

Carolyn Waugh Kinkade, Mireia Castillo-Martin, Anna Puzio-Kuter, Jun Yan, Thomas H. Foster, Hui Gao, Yvonne Sun, Xuesong Ouyang, William L. Gerald, Carlos Cordon-Cardo, Cory Abate-Shen

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Figure 1

Inhibition of AKT/mTOR and ERK MAPK signaling pathways with rapamycin and PD0325901.

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Inhibition of AKT/mTOR and ERK MAPK signaling pathways with rapamycin an...
(A) Diagram of the experimental strategy. Nkx3.1; Pten mutant mice develop low-grade and high-grade PIN (LGPIN and HGPIN, respectively) and ultimately adenocarcinoma as a consequence of aging, as well as androgen independence following castration. The trial design entailed enrolling androgen-intact or androgen-ablated mutant (or control) mice at approximately 10 months of age randomly into groups that were treated with rapamycin and/or PD0325901 (or vehicle) for 21 days (5 days on/2 days off), after which the mice were sacrificed (Sac) for analyses of end points (i.e., histology, prostate weights, cellular proliferation, immunohistochemistry, and Western blot analyses; Figures 3–6 and Table 1). AD, androgen-dependent; AI, androgen-independent. (B) Rapamycin and PD0325901 inhibit their respective targets in the prostate for up to 24 hours. Western blot analyses were performed using protein extracts prepared from the dorsolateral prostate of Nkx3.1+/—Pten+/— mutant mice (10 months) treated with rapamycin plus PD0325901 for the times indicated. Each group had 3 mice; Western blot analyses were done with at least 2 independent mice in each group, and representative samples are shown. (C–N) Rapamycin and PD0325901 lead to inhibition of target proteins in mouse prostate tissues in vivo. Immunohistochemical analyses were performed using the indicated antibodies on sections from the anterior prostate of Nkx3.1+/—Pten+/— mutant mice (10 months; androgen-intact) treated with rapamycin and/or PD0325901 (or vehicle) as indicated for 1 week. Scale bar: 100 μm.