Evidence map›Paper›PMID 24762959›Full record

ArticleBritish journal of cancer2014

Multipoint targeting of the PI3K/mTOR pathway in mesothelioma.

S Zhou, L Liu, H Li, G Eilers, Y Kuang, S Shi, Z Yan, X Li, J M Corson, F Meng and 4 more

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

Article in British journal of cancer, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 51 papers.

0numbers the graph read from it
0cells of the map it votes in
51citing papers in PubMed
8.2field-weighted citation impact, top 2% 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

51 citing papers in PubMed, 92 citations in OpenAlex.

  1. Trial
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  12. Target Therapy in Malignant Pleural Mesothelioma: Hope or Mirage?International journal of molecular sciences · 2023
    Review
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  20. Genomics and Functional Genomics of Malignant Pleural Mesothelioma.International journal of molecular sciences · 2020
    Review
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

14 authors at 5 institutions in 2 countries.

S Zhou1] Zhejiang Provincial Key Laboratory of Applied Enzymology, Department of Biotechnology and Biomedicine, Yangtze Delta Region Institute of Tsinghua University, Jiaxing, China [2] Department of Bioengineering, College of Biology and Chemical Engineering, Jiaxing University, Jiaxing, China.
L LiuZhejiang Provincial Key Laboratory of Applied Enzymology, Department of Biotechnology and Biomedicine, Yangtze Delta Region Institute of Tsinghua University, Jiaxing, China.
H LiZhejiang Provincial Key Laboratory of Applied Enzymology, Department of Biotechnology and Biomedicine, Yangtze Delta Region Institute of Tsinghua University, Jiaxing, China.
G EilersDepartment of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
Y KuangDepartment of Biochemistry and Molecular Biology, College of Life Sciences, Zhejiang Sci-Tech University, Hangzhou, China.
S ShiZhejiang Provincial Key Laboratory of Applied Enzymology, Department of Biotechnology and Biomedicine, Yangtze Delta Region Institute of Tsinghua University, Jiaxing, China.
Z YanZhejiang Provincial Key Laboratory of Applied Enzymology, Department of Biotechnology and Biomedicine, Yangtze Delta Region Institute of Tsinghua University, Jiaxing, China.
X LiZhejiang Provincial Key Laboratory of Applied Enzymology, Department of Biotechnology and Biomedicine, Yangtze Delta Region Institute of Tsinghua University, Jiaxing, China.
J M CorsonDepartment of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
F MengZhejiang Provincial Key Laboratory of Applied Enzymology, Department of Biotechnology and Biomedicine, Yangtze Delta Region Institute of Tsinghua University, Jiaxing, China.
H ZhouZhejiang Provincial Key Laboratory of Applied Enzymology, Department of Biotechnology and Biomedicine, Yangtze Delta Region Institute of Tsinghua University, Jiaxing, China.
Q ShengDepartment of Biochemistry and Molecular Biology, College of Life Sciences, Zhejiang Sci-Tech University, Hangzhou, China.
J A FletcherDepartment of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
W-B Ou1] Zhejiang Provincial Key Laboratory of Applied Enzymology, Department of Biotechnology and Biomedicine, Yangtze Delta Region Institute of Tsinghua University, Jiaxing, China [2] Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA [3] Department of Biochemistry and Molecular Biology, College of Life Sciences, Zhejiang Sci-Tech University, Hangzhou, China.
Tsinghua University · CNHarvard University · USZhejiang Sci-Tech University · CNBrigham and Women's Hospital · USJiaxing University · CN

Funding

No grant is acknowledged in the PubMed record.

6 · The paper itself

Abstract

backgroundMesothelioma is a notoriously chemotherapy-resistant neoplasm, as is evident in the dismal overall survival for patients with those of asbestos-associated disease. We previously demonstrated co-activation of multiple receptor tyrosine kinases (RTKs), including epidermal growth factor receptor (EGFR), MET, and AXL in mesothelioma cell lines, suggesting that these kinases could serve as novel therapeutic targets. Although clinical trials have not shown activity for EGFR inhibitors in mesothelioma, concurrent inhibition of various activated RTKs has pro-apoptotic and anti-proliferative effects in mesothelioma cell lines. Thus, we hypothesised that a coordinated network of multi-RTK activation contributes to mesothelioma tumorigenesis.

methodsActivation of PI3K/AKT/mTOR, Raf/MAPK, and co-activation of RTKs were evaluated in mesotheliomas. Effects of RTK and downstream inhibitors/shRNAs were assessed by measuring mesothelioma cell viability/growth, apoptosis, activation of signalling intermediates, expression of cell-cycle checkpoints, and cell-cycle alterations.

resultsWe demonstrate activation of the PI3K/AKT/p70S6K and RAF/MEK/MAPK pathways in mesothelioma, but not in non-neoplastic mesothelial cells. The AKT activation, but not MAPK activation, was dependent on coordinated activation of RTKs EGFR, MET, and AXL. In addition, PI3K/AKT/mTOR pathway inhibition recapitulated the anti-proliferative effects of concurrent inhibition of EGFR, MET, and AXL. Dual targeting of PI3K/mTOR by BEZ235 or a combination of RAD001 and AKT knockdown had a greater effect on mesothelioma proliferation and viability than inhibition of individual activated RTKs or downstream signalling intermediates. Inhibition of PI3K/AKT was also associated with MDM2-p53 cell-cycle regulation.

conclusionsThese findings show that PI3K/AKT/mTOR is a crucial survival pathway downstream of multiple activated RTKs in mesothelioma, underscoring that PI3K/mTOR is a compelling target for therapeutic intervention.

Indexed as

Phosphoinositide-3 Kinase InhibitorsAntineoplastic AgentsButadienesCell CycleCell Line, TumorChromonesDrug Screening Assays, AntitumorEnzyme ActivationEverolimusHumansImidazolesIndazolesMAP Kinase Signaling SystemMesotheliomaMolecular Targeted TherapyMorpholines2-(1H-indazol-4-yl)-6-(4-methanesulfonylpiperazin-1-ylmethyl)-4-morpholin-4-ylthieno(3,2-d)pyrimidine2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-oneAntineoplastic AgentsButadienesChromonesdactolisibEverolimusImidazolesIndazolesMorpholinesMTOR protein, humanNeoplasm ProteinsNitrilesPhosphatidylinositol 3-KinasesPhosphoinositide-3 Kinase InhibitorsProtein Kinase InhibitorsQuinolinesraf KinasesReceptor Protein-Tyrosine KinasesRNA, Small InterferingSirolimusSulfonamidesTOR Serine-Threonine KinasesU 0126

Identifiers

PMID24762959
PMCPMC4021537
OpenAlexW2035905423

What OpenQuestion holds

Textmetadata
LicenceCC BY-NC-SA
Read underepoch 390

Registered trials

None linked

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.