Oncotarget

Research Papers:

Inhibition of the PI3K/AKT/mTOR pathway activates autophagy and compensatory Ras/Raf/MEK/ERK signalling in prostate cancer

Dominika E. Butler, Christopher Marlein, Hannah F. Walker, Fiona M. Frame, Vincent M. Mann, Matthew S. Simms, Barry R. Davies, Anne T. Collins and Norman J. Maitland _

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Oncotarget. 2017; 8:56698-56713. https://doi.org/10.18632/oncotarget.18082

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Abstract

Dominika E. Butler1, Christopher Marlein2, Hannah F. Walker1, Fiona M. Frame1, Vincent M. Mann3, Matthew S. Simms4,5, Barry R. Davies6, Anne T. Collins1 and Norman J. Maitland1

1The Cancer Research Unit, Department of Biology, University of York, York YO10 5DD, UK

2Norwich Medical School, University of East Anglia, Norwich NR4 7TJ, UK

3Gastroenterology Research Department, Hull Royal Infirmary, Hull HU3 2JZ, UK

4Department of Urology, Castle Hill Hospital (Hull & East Yorkshire Hospital NHS Trust), Cottingham HU16 5JQ, UK

5Hull York Medical School, University of York, York YO10 5DD, UK

6AstraZeneca, Cancer Research UK Cambridge Institute, Cambridge CB2 0RE, UK

Correspondence to:

Norman J. Maitland, email: [email protected]

Keywords: prostate cancer, AKT, mTOR, RAS, MAPK signalling, autophagy

Received: May 27, 2016    Accepted: April 24, 2017    Published: May 23, 2017

ABSTRACT

The PI3K/AKT/mTOR pathway is frequently activated in advanced prostate cancer, due to loss of the tumour suppressor PTEN, and is an important axis for drug development. We have assessed the molecular and functional consequences of pathway blockade by inhibiting AKT and mTOR kinases either in combination or as individual drug treatments. In established prostate cancer cell lines, a decrease in cell viability and in phospho-biomarker expression was observed. Although apoptosis was not induced, a G1 growth arrest was observed in PTEN null LNCaP cells, but not in BPH1 or PC3 cells. In contrast, when the AKT inhibitor AZD7328 was applied to patient-derived prostate cultures that retained expression of PTEN, activation of a compensatory Ras/MEK/ERK pathway was observed. Moreover, whilst autophagy was induced following treatment with AZD7328, cell viability was less affected in the patient-derived cultures than in cell lines. Surprisingly, treatment with a combination of both AZD7328 and two separate MEK1/2 inhibitors further enhanced phosphorylation of ERK1/2 in primary prostate cultures. However, it also induced irreversible growth arrest and senescence.

Ex vivo treatment of a patient-derived xenograft (PDX) of prostate cancer with a combination of AZD7328 and the mTOR inhibitor KU-0063794, significantly reduced tumour frequency upon re-engraftment of tumour cells.

The results demonstrate that single agent targeting of the PI3K/AKT/mTOR pathway triggers activation of the Ras/MEK/ERK compensatory pathway in near-patient samples. Therefore, blockade of one pathway is insufficient to treat prostate cancer in man.


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