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

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


Dominika E. Butler

Christopher Marlein

Hannah F. Walker

Fiona M. Frame

Vincent M. Mann

Matthew S. Simms

Barry R. Davies

Anne T. Collins

Norman J. Maitland


Fiona Frame


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.


Butler, D. E., Marlein, C., Walker, H. F., Frame, F. M., Mann, V. M., Simms, M. S., …Maitland, N. J. (2017). Inhibition of the PI3K/AKT/mTOR pathway activates autophagy and compensatory Ras/Raf/MEK/ERK signalling in prostate cancer. Oncotarget, 8(34), 56698-56713.

Journal Article Type Article
Acceptance Date Apr 23, 2017
Online Publication Date May 23, 2017
Publication Date Aug 22, 2017
Deposit Date Jun 20, 2019
Publicly Available Date Jun 21, 2019
Journal Oncotarget
Print ISSN 1949-2553
Publisher Impact Journals
Peer Reviewed Peer Reviewed
Volume 8
Issue 34
Pages 56698-56713
Keywords Prostate cancer; AKT; mTOR; RAS; MAPK signalling; Autophagy
Public URL
Publisher URL[]=18082&path[]=57942
Additional Information I don't know if it is open access


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Copyright Statement
Copyright: Butler et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License 3.0<br /> (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source<br /> are credited.

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