Evidence map›Paper›PMID 31388935›Full record

ArticleBreast cancer research and treatment2019

Multi-targeted kinase inhibition alleviates mTOR inhibitor resistance in triple-negative breast cancer.

Jichao He, Ronan P McLaughlin, Vera van der Noord, John A Foekens, John W M Martens, Gerard van Westen, Yinghui Zhang, Bob van de Water

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

Article in Breast cancer research and treatment, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 17 papers, 1 of them a synthesis that pooled it.

0numbers the graph read from it
0cells of the map it votes in
17citing papers in PubMed, 1 pooled it
2.1field-weighted citation impact, top 12% 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

17 citing papers in PubMed, 1 synthesis or guideline pooled it, 38 citations in OpenAlex.

  1. Pooled it
  2. Review
  3. Article
  4. Review
  5. In Silico Analysis of the Effect ofMedicina (Kaunas, Lithuania) · 2023
    Article
  6. Article
  7. Article
  8. Review
  9. Article
  10. Heterogeneity within molecular subtypes of breast cancer.American journal of physiology. Cell physiology · 2021
    Review
  11. Review
  12. Article
  13. Article
  14. Targeting ERK-Hippo Interplay in Cancer Therapy.International journal of molecular sciences · 2020
    Review
  15. Article
  16. Article
  17. 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

8 authors at 2 institutions in 1 country.

Jichao HeDivision of Drug Discovery and Safety, Leiden Academic Centre for Drug Research, Leiden University, 2300 RA, Leiden, The Netherlands.
Ronan P McLaughlinDivision of Drug Discovery and Safety, Leiden Academic Centre for Drug Research, Leiden University, 2300 RA, Leiden, The Netherlands.
Vera van der NoordDivision of Drug Discovery and Safety, Leiden Academic Centre for Drug Research, Leiden University, 2300 RA, Leiden, The Netherlands.
John A FoekensDepartment of Medical Oncology and Cancer Genomic Netherlands, Erasmus MC Cancer Institute, Erasmus Medical Centre, 3000 CA, Rotterdam, The Netherlands.
John W M MartensDepartment of Medical Oncology and Cancer Genomic Netherlands, Erasmus MC Cancer Institute, Erasmus Medical Centre, 3000 CA, Rotterdam, The Netherlands.
Gerard van WestenDivision of Drug Discovery and Safety, Leiden Academic Centre for Drug Research, Leiden University, 2300 RA, Leiden, The Netherlands.
Yinghui ZhangDivision of Drug Discovery and Safety, Leiden Academic Centre for Drug Research, Leiden University, 2300 RA, Leiden, The Netherlands.
Bob van de WaterDivision of Drug Discovery and Safety, Leiden Academic Centre for Drug Research, Leiden University, 2300 RA, Leiden, The Netherlands. b.water@lacdr.leidenuniv.nl.ORCID http://orcid.org/0000-0002-5839-2380
Leiden University · NLErasmus MC Cancer Institute · NL

Funding

China Scholarship Council 201407060007Dutch Cancer Society 2011-5124Dutch Scientific Council NWO domain AES Veni 14410European Research Council 322737
6 · The paper itself

Abstract

purposeOwing to its genetic heterogeneity and acquired resistance, triple-negative breast cancer (TNBC) is not responsive to single-targeted therapy, causing disproportional cancer-related death worldwide. Combined targeted therapy strategies to block interactive oncogenic signaling networks are being explored for effective treatment of the refractory TNBC subtype.

methodsA broad kinase inhibitor screen was applied to profile the proliferative responses of TNBC cells, revealing resistance of TNBC cells to inhibition of the mammalian target of rapamycin (mTOR). A systematic drug combination screen was subsequently performed to identify that AEE788, an inhibitor targeting multiple receptor tyrosine kinases (RTKs) EGFR/HER2 and VEGFR, synergizes with selective mTOR inhibitor rapamycin as well as its analogs (rapalogs) temsirolimus and everolimus to inhibit TNBC cell proliferation.

resultsThe combination treatment with AEE788 and rapalog effectively inhibits phosphorylation of mTOR and 4EBP1, relieves mTOR inhibition-mediated upregulation of cyclin D1, and maintains suppression of AKT and ERK signaling, thereby sensitizing TNBC cells to the rapalogs. siRNA validation of cheminformatics-based predicted AEE788 targets has further revealed the mTOR interactive RPS6K members (RPS6KA3, RPS6KA6, RPS6KB1, and RPS6KL1) as synthetic lethal targets for rapalog combination treatment.

conclusionsmTOR signaling is highly activated in TNBC tumors. As single rapalog treatment is insufficient to block mTOR signaling in rapalog-resistant TNBC cells, our results thus provide a potential multi-kinase inhibitor combinatorial strategy to overcome mTOR-targeted therapy resistance in TNBC cells.

Indexed as

Drug Resistance, NeoplasmAntineoplastic AgentsBiomarkersCell Line, TumorCell ProliferationDose-Response Relationship, DrugDrug Screening Assays, AntitumorExtracellular Signal-Regulated MAP KinasesFemaleHumansPhosphorylationProtein Kinase InhibitorsProto-Oncogene Proteins c-aktSignal TransductionTOR Serine-Threonine KinasesTriple Negative Breast NeoplasmsAntineoplastic AgentsBiomarkersExtracellular Signal-Regulated MAP KinasesMTOR protein, humanProtein Kinase InhibitorsProto-Oncogene Proteins c-aktTOR Serine-Threonine KinasesDrug resistancemTOR-targeted therapyMulti-kinase inhibitorPolypharmacologyTriple-negative breast cancer (TNBC)

Identifiers

PMID31388935
PMCPMC6797661
OpenAlexW2966274794

What Socratic holds

Textmetadata
LicenceCC BY
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 Socratic graph.