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

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.

Tumor heterogeneity and therapy resistance - implications for future treatments of prostate cancer

“…In addition, using a panel of cell lines may also not be a great improvement because results from experiments in cell lines have been seen here and in other studies to be quite different from primary cells [26][27][28] . Cells in primary cultures have compensatory signaling pathways that have been lost in cell lines, and so an inhibitor that works well in cell lines may be less effective or ineffective in primary cultures [28] . This is one explanation for such high attrition rate in the drug pipeline; weak, incomplete, unrepresentative or inappropriate models.…”

Testis‐specific protein, Y‐linked 1 activates PI3K/AKT and RAS signaling pathways through suppressing IGFBP3 expression during tumor progression

“…In addition, we found that TSPY1 contributed to the upregulation of p‐RAF1, p‐MEK1/2, and p‐ERK1/2 in the RAS signaling pathway in both A549 and HepG2 cells and that the JUN protein level was consequently increased (Figures B and ). Considering the significance of PI3K/AKT/mTOR/BCL2 and RAS/RAF/MEK/ERK/JUN signaling pathways in cell proliferation, cycle, invasiveness, and apoptosis, we propose that TSPY1 affects cell biological phenotypes probably through a cross‐talk network that involves the molecules with functional regulation of both PI3K/AKT and RAS signaling pathways.…”

“…C, Western blot analysis showed higher levels of 4 key proteins (p-RAF-1, p-MEK1/2, p-ERK1/2, and JUN) of the RAS signaling pathway in A549 and HepG2 cells with IGFBP3 knockdown, relative to controls (shNC and siNC) signaling pathways, and this promotion depended on the inhibition of TSPY1 on IGFBP3 expression. The PI3K/AKT and RAS signaling pathways are key signal transduction components in the regulation of cell growth, cell differentiation, cell cycle, apoptosis, and metastasis, [22][23][24][25][26] and recent reports show that deregulated activation of the 2 signalings is frequently observed in many cancers. [29][30][31] Therefore, our findings provided a potential common mechanism of TSPY1's function as an oncogene in the tumor process.…”

Andrographolide Induces Autophagic Cell Death and Inhibits Invasion and Metastasis of Human Osteosarcoma Cells in An Autophagy-Dependent Manner

“…mTOR functions at the center of various signaling pathways, and the classic PI3K/Akt/mTOR pathway regulates autophagy mainly through the activation of mTOR [34]. PtdIns(3, 4)P2 and PtdIns(3, 4,5) P3, produced by class I PI3K, can interact with the pleckstrin homology domain of Akt, activating the Akt signaling pathway, which indirectly activates mTOR to inhibit autophagy [35].…”