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2017 ; 8
(34
): 56698-56713
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Inhibition of the PI3K/AKT/mTOR pathway activates autophagy and compensatory
Ras/Raf/MEK/ERK signalling in prostate cancer
#MMPMID28915623
Butler DE
; Marlein C
; Walker HF
; Frame FM
; Mann VM
; Simms MS
; Davies BR
; Collins AT
; Maitland NJ
Oncotarget
2017[Aug]; 8
(34
): 56698-56713
PMID28915623
show ga
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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