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Targeting of the PI3K/AKT/mTOR pathway in human prostate cancer

Butler, Dominika Ewelina (2014) Targeting of the PI3K/AKT/mTOR pathway in human prostate cancer. PhD thesis, University of York.

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The tumour suppressor PTEN is frequently lost in advanced prostate cancer leading to over-activation of the PI3K/AKT/mTOR pathway. Therefore targeting of the PI3K signalling with pathway-specific inhibitors has been proposed as a therapeutic strategy. Inhibition of AKT and mTOR kinases in prostate cancer cell lines showed a decrease in cell viability and reduction in phospho-biomarkers expression. Although apoptosis was not induced, a decrease in cell migration and G1 cell growth arrest were observed in LNCaP cells. However, in primary prostate cultures activation of the Ras/MEK/ERK compensatory pathway was observed following treatment with AKTi. Moreover, cell viability was less affected than in cell lines and autophagy was induced following treatment with AKTi. Surprisingly, treatment with a combination of AKTi and MEK1/2 inhibitors (MEK1/2i and RO-512) did not reduce phosphorylation of ERK1/2 in primary prostate cultures, but irreversible growth arrest-senescence, was evident. Additionally, ex vivo treatment of a ‘near-patient’ prostate xenograft with a combination of AKTi and mTORi significantly reduced tumour frequency. These results demonstrate that targeting the PI3K/AKT/mTOR pathway triggers activation of the Ras/MEK/ERK compensatory pathway and therefore blockade of one pathway is not sufficient to treat prostate cancer. This study also highlights the importance of using patient-derived tumour cells in preclinical assessment of new drugs rather than relying solely on cancer cell lines.

Item Type: Thesis (PhD)
Keywords: prostate cancer, AKT, mTOR, autophagy
Academic Units: The University of York > Biology (York)
Identification Number/EthosID: uk.bl.ethos.643655
Depositing User: Mrs Dominika Ewelina Butler
Date Deposited: 17 Apr 2015 14:45
Last Modified: 08 Sep 2016 13:32
URI: http://etheses.whiterose.ac.uk/id/eprint/8531

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