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Title: Targeting of the PI3K/AKT/mTOR pathway in human prostate cancer
Author: Butler, Dominika Ewelina
ISNI:       0000 0004 5355 0428
Awarding Body: University of York
Current Institution: University of York
Date of Award: 2014
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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.
Supervisor: Maitland, Norman J. ; Davies, Barry R. Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available