Dataset Information

Evidence of mTOR Activation by an AKT-Independent Mechanism Provides Support for the Combined Treatment of PTEN-Deficient Prostate Tumors with mTOR and AKT Inhibitors.

ABSTRACT: Activation of the phosphoinositide 3-kinase pathway is commonly observed in human prostate cancer. Loss of function of phosphatase and tensin homolog (PTEN) is associated with the activation of AKT and mammalian target of rapamycin (mTOR) in many cancer cell lines as well as in other model systems. However, activation of mTOR is also dependent of kinases other than AKT. Here, we show that activation of mTOR is not dependent on AKT in a prostate-specific PTEN-deficient mouse model of prostate cancer. Pathway bifurcation of AKT and mTOR was noted in both mouse and human prostate tumors. We demonstrated for the first time that cotargeting mTOR and AKT with ridaforolimus/MK-8669 and M1K-2206, respectively, delivers additive antitumor effects in vivo when compared to single agents. Our preclinical data suggest that the combination of AKT and mTOR inhibitors might be more effective in treating prostate cancer patients than current treatment regimens or either treatment alone.

SUBMITTER: Zhang W

PROVIDER: S-EPMC3542838 | biostudies-literature | 2012 Dec

REPOSITORIES: biostudies-literature

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Publications

Evidence of mTOR Activation by an AKT-Independent Mechanism Provides Support for the Combined Treatment of PTEN-Deficient Prostate Tumors with mTOR and AKT Inhibitors.

Zhang Weisheng W Haines Brian B BB Efferson Clay C Zhu Joe J Ware Chris C Kunii Kaiko K Tammam Jennifer J Angagaw Minilik M Hinton Marlene C MC Keilhack Heike H Paweletz Cloud P CP Zhang Theresa T Winter Chris C Sathyanarayanan Sriram S Cheng Jonathan J Zawel Leigh L Fawell Stephen S Gilliland Gary G Majumder Pradip K PK

Translational oncology 20121201 6

Activation of the phosphoinositide 3-kinase pathway is commonly observed in human prostate cancer. Loss of function of phosphatase and tensin homolog (PTEN) is associated with the activation of AKT and mammalian target of rapamycin (mTOR) in many cancer cell lines as well as in other model systems. However, activation of mTOR is also dependent of kinases other than AKT. Here, we show that activation of mTOR is not dependent on AKT in a prostate-specific PTEN-deficient mouse model of prostate can ...[more]

PMID: 23323157

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Project description:To model the effect of Pten loss on breast cancer, we deleted Pten using a floxed allele and the deleter lines MMTV-Cre(NLST), which targets stem/bi-potent progenitor cells, and WAP-Cre, which targets CD24-positive, pregnancy-identified stem cells/alveolar progenitors. Mammary tumors were detected in WAP-Cre:Ptenf/f females with a latency of 15.2 months. By 18 months, nearly all mice had succumbed to cancer. MMTV-Cre:Ptenf/f mice developed mammary tumors after a longer latency of 26.4 months and reduced penetrance (70%) compared to WAP-Cre:Ptenf/f mice. Tumors from both models were heterogeneous, consisting primarily of differentiated adenocarcinoma (adenomyoepithelioma; ~70%) and adenosquamous carcinoma (20-25%). In addition, a small fraction of tumors was classified as acinar and poorly differentiated adenocarcinoma (4-7%) and adenosarcoma (3-4%). To test the consequences of combined Pten and p53 gene mutation on breast cancer, we deleted both genes via MMTV-Cre or WAP-Cre. Kaplan-Meier tumor free survival curves revealed that WAP-Cre:Ptenf/f:p53f/f and MMTV-Cre:Ptenf/f:p53f/f females developed tumors with reduced latency of 11.3 and 9.8 months, compared with 15.2, 26.4, and 16.9 months for single-mutant WAP-Cre:Ptenf/f, MMTV-Cre:Ptenf/f or MMTV-Cre:p53f/f mice, respectively. In contrast to the heterogeneity of Pten tumors and small percentage of adenosarcomas in these mice, ~70% of Pten:p53 lesions were histologically classified as adeno-sacrcomatoid-like or mesenchymal-like breast cancer, with the rest exhibiting mixed mesenchymal plus adenocarcinomas and differentiated adenocarcinomas. The adeno-sacrcomatoid-like tumors expressed the mesenchymal markers vimentin, K5, SMA, N-cadherin and desmin but not ER, as well as islands of luminal-like K18 expressing cells surrounded by a layer of K14-positive cells. We used microarrays to detect differentially expressed genes in the Pten:p53 double-knock-out vs Pten or p53 single deletions Total RNA was extracted from tumors developed by double Trizol method and hybridized on Affymetrix microarrays.

Dataset Information

Evidence of mTOR Activation by an AKT-Independent Mechanism Provides Support for the Combined Treatment of PTEN-Deficient Prostate Tumors with mTOR and AKT Inhibitors.

Publications

Evidence of mTOR Activation by an AKT-Independent Mechanism Provides Support for the Combined Treatment of PTEN-Deficient Prostate Tumors with mTOR and AKT Inhibitors.

Similar Datasets

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