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

Overview of attention for article published in Oncotarget, May 2017
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Title
Inhibition of the PI3K/AKT/mTOR pathway activates autophagy and compensatory Ras/Raf/MEK/ERK signalling in prostate cancer
Published in
Oncotarget, May 2017
DOI 10.18632/oncotarget.18082
Pubmed ID
Authors

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

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.

Twitter Demographics

The data shown below were collected from the profile of 1 tweeter who shared this research output. Click here to find out more about how the information was compiled.

Mendeley readers

The data shown below were compiled from readership statistics for 73 Mendeley readers of this research output. Click here to see the associated Mendeley record.

Geographical breakdown

Country Count As %
Unknown 73 100%

Demographic breakdown

Readers by professional status Count As %
Student > Master 14 19%
Student > Bachelor 10 14%
Student > Ph. D. Student 10 14%
Researcher 9 12%
Student > Doctoral Student 6 8%
Other 8 11%
Unknown 16 22%
Readers by discipline Count As %
Biochemistry, Genetics and Molecular Biology 23 32%
Medicine and Dentistry 12 16%
Agricultural and Biological Sciences 6 8%
Pharmacology, Toxicology and Pharmaceutical Science 2 3%
Computer Science 1 1%
Other 6 8%
Unknown 23 32%

Attention Score in Context

This research output has an Altmetric Attention Score of 1. This is our high-level measure of the quality and quantity of online attention that it has received. This Attention Score, as well as the ranking and number of research outputs shown below, was calculated when the research output was last mentioned on 17 September 2017.
All research outputs
#10,443,668
of 11,779,850 outputs
Outputs from Oncotarget
#7,445
of 11,474 outputs
Outputs of similar age
#224,962
of 265,979 outputs
Outputs of similar age from Oncotarget
#405
of 685 outputs
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