Evidence map›Paper›PMID 25950487›Full record

ArticleCell death & disease2015

Inhibition of autophagy sensitizes malignant pleural mesothelioma cells to dual PI3K/mTOR inhibitors.

N Echeverry, G Ziltener, D Barbone, W Weder, R A Stahel, V C Broaddus, E Felley-Bosco

Open access · goldAbstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Cell death & disease, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 28 papers.

0numbers the graph read from it
0cells of the map it votes in
28citing papers in PubMed
6.0field-weighted citation impact, top 3% of its field
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

28 citing papers in PubMed, 48 citations in OpenAlex.

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4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

7 authors at 3 institutions in 2 countries.

N EcheverryLaboratory of Molecular Oncology, Clinic of Oncology, University Hospital of Zürich, Häldeliweg 4, Zürich 8044, Switzerland.
G ZiltenerLaboratory of Molecular Oncology, Clinic of Oncology, University Hospital of Zürich, Häldeliweg 4, Zürich 8044, Switzerland.
D BarboneDepartment of Medicine, Division of Pulmonary, San Francisco General Hospital, University of California San Francisco, San Francisco, CA 94110, USA.
W WederDivision of Thoracic Surgery, University Hospital Zürich, Zürich, Switzerland.
R A StahelLaboratory of Molecular Oncology, Clinic of Oncology, University Hospital of Zürich, Häldeliweg 4, Zürich 8044, Switzerland.
V C BroaddusDepartment of Medicine, Division of Pulmonary, San Francisco General Hospital, University of California San Francisco, San Francisco, CA 94110, USA.
E Felley-BoscoLaboratory of Molecular Oncology, Clinic of Oncology, University Hospital of Zürich, Häldeliweg 4, Zürich 8044, Switzerland.
University of Zurich · CHUniversity of California, San Francisco · USUniversity Hospital of Zurich · CH

Funding

No grant is acknowledged in the PubMed record.

6 · The paper itself

Abstract

Malignant pleural mesothelioma (MPM) originates in most of the cases from chronic inflammation of the mesothelium due to exposure to asbestos fibers. Given the limited effect of chemotherapy, a big effort is being made to find new treatment options. The PI3K/mTOR pathway was reported to be upregulated in MPM. We tested the cell growth inhibition properties of two dual PI3K/mTOR inhibitors NVP-BEZ235 and GDC-0980 on 19 MPM cell lines. We could identify resistant and sensitive lines; however, there was no correlation to the downregulation of PI3K/mTOR activity markers. As a result of mTOR inhibition, both drugs efficiently induced long-term autophagy but not cell death. Autophagy blockade by chloroquine in combination with the dual PI3K/mTOR inhibitors significantly induced caspase-independent cell death involving RIP1 in the sensitive cell line SPC212. Cell death in the resistant cell line Mero-82 was less pronounced, and it was not induced via RIP1-dependent mechanism, suggesting the involvement of RIP1 downstream effectors. Cell death induction was confirmed in 3D systems. Based on these results, we identify autophagy as one of the main mechanisms of cell death resistance against dual PI3K/mTOR inhibitors in MPM. As PI3K/mTOR inhibitors are under investigation in clinical trials, these results may help interpreting their outcome and suggest ways for intervention.

Indexed as

Phosphoinositide-3 Kinase InhibitorsAutophagyBridged Bicyclo Compounds, HeterocyclicCell ProliferationDrug SynergismHumansImidazolesLung NeoplasmsMesotheliomaMesothelioma, MalignantPhosphatidylinositol 3-KinasesPhosphorylationPleural NeoplasmsProtein Kinase InhibitorsPyrimidinesQuinolines1-(4-((2-(2-aminopyrimidin-5-yl)-7-methyl-4-morpholinothieno(3,2-d)pyrimidin-6-yl)methyl)piperazin-1-yl)-2-hydroxypropan-1-oneBridged Bicyclo Compounds, HeterocyclicdactolisibImidazolesMTOR protein, humanPhosphatidylinositol 3-KinasesPhosphoinositide-3 Kinase InhibitorsProtein Kinase InhibitorsPyrimidinesQuinolinesTOR Serine-Threonine Kinases

Identifiers

PMID25950487
PMCPMC4669703
OpenAlexW262498496

What OpenQuestion holds

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LicenceCC BY
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Registered trials

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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.