Evidence map›Paper›PMID 27435925›Full record

ArticleNeoplasia (New York, N.Y.)2016

Upstream and Downstream Co-inhibition of Mitogen-Activated Protein Kinase and PI3K/Akt/mTOR Pathways in Pancreatic Ductal Adenocarcinoma.

Matthew H Wong, Aiqun Xue, Robert C Baxter, Nick Pavlakis, Ross C Smith

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

Article in Neoplasia (New York, N.Y.), 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 27 papers.

0numbers the graph read from it
0cells of the map it votes in
27citing papers in PubMed
3.0field-weighted citation impact, top 7% 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

27 citing papers in PubMed, 39 citations in OpenAlex.

  1. Review
  2. Article
  3. Review
  4. Review
  5. Review
  6. Review
  7. Article
  8. Review
  9. Review
  10. Article
  11. Review
  12. Article
  13. Knockdown of the DJ-1 (Molecular therapy oncolytics · 2021
    Article
  14. Article
  15. Targeting MutantBiomedicines · 2020
    Review
  16. Article
  17. Article
  18. Article
  19. Article
  20. Article
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

5 authors at 3 institutions in 1 country.

Matthew H WongCancer Surgery Research Laboratory, Kolling Institute of Medical Research, University of Sydney, Sydney, NSW, Australia; Department of Medical Oncology, Gosford Hospital, Sydney, NSW, Australia.
Aiqun XueCancer Surgery Research Laboratory, Kolling Institute of Medical Research, University of Sydney, Sydney, NSW, Australia.
Robert C BaxterHormones and Cancer, Kolling Institute of Medical Research, University of Sydney, Sydney, NSW, Australia.
Nick PavlakisDepartment of Medical Oncology, Royal North Shore Hospital, University of Sydney, Sydney, NSW, Australia.
Ross C SmithCancer Surgery Research Laboratory, Kolling Institute of Medical Research, University of Sydney, Sydney, NSW, Australia; Department of Upper Gastrointestinal Surgery, Royal North Shore Hospital, University of Sydney, Sydney, NSW, Australia.
University of Sydney · AUGosford Hospital · AURoyal North Shore Hospital · AU

Funding

No grant is acknowledged in the PubMed record.

6 · The paper itself

Abstract

backgroundExtensive cross talk exists between PI3K/Akt/mTOR and mitogen-activated protein kinase (MAPK) pathways, and both are upregulated in pancreatic ductal adenocarcinoma (PDAC). Our previous study suggested that epidermal growth factor receptor inhibitor erlotinib which acts upstream of these pathways acts synergistically with PI3K inhibitors in PDAC. Horizontal combined blockade upstream and downstream of these two pathways is therefore explored.

methodsErlotinib paired with PI3K inhibitor (BYL719) was tested against erlotinib plus dual PI3K/mTOR inhibitor BEZ-235, and MEK inhibitor (PD98059) plus BEZ235, on five primary PDAC cell lines and on two pairs of parent and erlotinib-resistant (ER) cell lines. A range of in vitro assays including cell proliferation, Western blotting, migration, clonogenic, cell cycle, and apopotic assays was used to test for the efficacy of combined blockade.

resultsDual downstream blockade of the MAPK and PAM pathways was more effective in attenuating downstream molecular signals. Synergy was demonstrated for erlotinib and BEZ235 and for PD-98059 and BEZ-235. This resulted in a trend of increased growth cell cycle arrest, apoptosis, cell proliferation, and colony and migration suppression. This combination showed more efficacy in cell lines with acquired resistance to erlotinib.

conclusionsThe additional mTOR blockade provided by BEZ235 in combined blockade resulted in increased anticancer effect. The hypersensitivity of ER cell lines to additional mTOR blockade suggested PAM pathway oncogenic dependence via mTOR. Dual downstream combined blockade of MAPK and PAM pathways with MEK and PI3K/mTOR inhibitor appeared most effective and represents an attractive therapeutic strategy against pancreatic cancer and its associated drug resistance.

Indexed as

Phosphoinositide-3 Kinase InhibitorsAntineoplastic AgentsAntineoplastic Combined Chemotherapy ProtocolsApoptosisCarcinoma, Pancreatic DuctalCell Cycle CheckpointsCell Line, TumorCell MovementCell ProliferationDrug Resistance, NeoplasmDrug SynergismErlotinib HydrochlorideFlavonoidsHumansImidazolesMAP Kinase Signaling System2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-oneAlpelisibAntineoplastic AgentsdactolisibErlotinib HydrochlorideFlavonoidsImidazolesMitogen-Activated Protein KinasesMTOR protein, humanPhosphoinositide-3 Kinase InhibitorsProto-Oncogene Proteins c-aktQuinolinesThiazolesTOR Serine-Threonine Kinases

Identifiers

PMID27435925
PMCPMC5022074
OpenAlexW2505309300

What OpenQuestion holds

Textmetadata
LicenceCC BY-NC-ND
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.