Evidence map›Paper›PMID 32094923›Full record

ArticleNature chemical biology2020

A drug discovery platform to identify compounds that inhibit EGFR triple mutants.

Punit Saraon, Jamie Snider, Yannis Kalaidzidis, Leanne E Wybenga-Groot, Konstantin Weiss, Ankit Rai, Nikolina Radulovich, Luka Drecun, Nika Vučković, Adriana Vučetić and 28 more

Open access · bronzeAbstract read
In one paragraph

Article in Nature chemical biology, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 18 papers, 1 of them a synthesis that pooled it.

0numbers the graph read from it
0cells of the map it votes in
18citing papers in PubMed, 1 pooled it
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

18 citing papers in PubMed, 1 synthesis or guideline pooled it, 37 citations in OpenAlex.

  1. Pooled it
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  15. Tackling Drug Resistance in EGFR Exon 20 Insertion Mutant Lung Cancer.Pharmacogenomics and personalized medicine · 2021
    Review
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4 · The record

Corrections and comments

5 · Who and what money

Authors and funding

38 authors at 9 institutions in 6 countries.

Punit Saraon *Donnelly Centre, University of Toronto, Toronto, Ontario, Canada.
Jamie Snider *Donnelly Centre, University of Toronto, Toronto, Ontario, Canada.
Yannis KalaidzidisMax Planck Institute of Molecular Cell Biology and Genetics, Dresden, Germany.ORCID http://orcid.org/0000-0002-6137-1193
Leanne E Wybenga-GrootSPARC BioCentre, The Hospital for Sick Children, Toronto, Ontario, Canada.
Konstantin WeissDonnelly Centre, University of Toronto, Toronto, Ontario, Canada.
Ankit RaiCell Biology, Department of Biology, Faculty of Science, Utrecht University, Utrecht, the Netherlands.ORCID http://orcid.org/0000-0002-3732-3597
Nikolina RadulovichPrincess Margaret Cancer Centre, University Health Network, University of Toronto, Toronto, Ontario, Canada.
Luka DrecunDonnelly Centre, University of Toronto, Toronto, Ontario, Canada.
Nika VučkovićDonnelly Centre, University of Toronto, Toronto, Ontario, Canada.
Adriana VučetićDonnelly Centre, University of Toronto, Toronto, Ontario, Canada.
Victoria WongDonnelly Centre, University of Toronto, Toronto, Ontario, Canada.
Brigitte ThériaultDrug Discovery Program, Ontario Institute for Cancer Research, Toronto, Ontario, Canada.
Nhu-An PhamPrincess Margaret Cancer Centre, University Health Network, University of Toronto, Toronto, Ontario, Canada.
Jin H ParkDepartment of Pharmacology and Cancer Biology Institute, Yale University, New Haven, CT, USA.
Alessandro DattiNetwork Biology Collaborative Centre, Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada.
Jenny WangNetwork Biology Collaborative Centre, Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada.
Shivanthy PathmanathanDonnelly Centre, University of Toronto, Toronto, Ontario, Canada.
Farzaneh AboualizadehDonnelly Centre, University of Toronto, Toronto, Ontario, Canada.
Anna LyakishevaDonnelly Centre, University of Toronto, Toronto, Ontario, Canada.
Zhong YaoDonnelly Centre, University of Toronto, Toronto, Ontario, Canada.
Yuhui WangPrincess Margaret Cancer Centre, University Health Network, University of Toronto, Toronto, Ontario, Canada.
Babu JosephDrug Discovery Program, Ontario Institute for Cancer Research, Toronto, Ontario, Canada.
Ahmed AmanDrug Discovery Program, Ontario Institute for Cancer Research, Toronto, Ontario, Canada.
Michael F MoranPeter Gilgan Centre for Research and Learning, Hospital for Sick Children, Toronto, Ontario, Canada.
Michael PrakeschDrug Discovery Program, Ontario Institute for Cancer Research, Toronto, Ontario, Canada.
Gennady PodaDrug Discovery Program, Ontario Institute for Cancer Research, Toronto, Ontario, Canada.
Richard MarcellusDrug Discovery Program, Ontario Institute for Cancer Research, Toronto, Ontario, Canada.
David UehlingDrug Discovery Program, Ontario Institute for Cancer Research, Toronto, Ontario, Canada.
Miroslav SamaržijaDepartment for Lung Diseases Jordanovac, Clinical Hospital Centre Zagreb, University of Zagreb, Zagreb, Croatia.
Marko JakopovićDepartment for Lung Diseases Jordanovac, Clinical Hospital Centre Zagreb, University of Zagreb, Zagreb, Croatia.
Ming-Sound TsaoPrincess Margaret Cancer Centre, University Health Network, University of Toronto, Toronto, Ontario, Canada.
Frances A ShepherdDivision of Medical Oncology and Hematology, Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada.
Adrian SacherPrincess Margaret Cancer Centre, University Health Network, University of Toronto, Toronto, Ontario, Canada.
Natasha LeighlPrincess Margaret Cancer Centre, University Health Network, University of Toronto, Toronto, Ontario, Canada.
Anna AkhmanovaCell Biology, Department of Biology, Faculty of Science, Utrecht University, Utrecht, the Netherlands.ORCID http://orcid.org/0000-0002-9048-8614
Rima Al-AwarDrug Discovery Program, Ontario Institute for Cancer Research, Toronto, Ontario, Canada.
Marino ZerialMax Planck Institute of Molecular Cell Biology and Genetics, Dresden, Germany.ORCID http://orcid.org/0000-0002-7490-4235
Igor StagljarDonnelly Centre, University of Toronto, Toronto, Ontario, Canada. igor.stagljar@utoronto.ca.ORCID http://orcid.org/0000-0002-5260-3327
University of Toronto · CAOntario Institute for Cancer Research · CAUniversity Health Network · CAMax Planck Institute of Molecular Cell Biology and Genetics · DEMount Sinai Hospital · CAUniversity Hospital Centre Zagreb · HRUtrecht University · NLCornell University · USHospital for Sick Children · CA

Funding

Understanding Signaling by Non-Canonical Receptor Tyrosine KinasesR35GM122485 · NIGMS · YALE UNIVERSITY · PI Mark A Lemmon · 2017 to 2026
$7.9M
Understanding EGF receptor activation by growth factors and oncogenic mutationsR01CA198164 · NCI · YALE UNIVERSITY · PI FERGUSON, KATHRYN M, LEMMON, MARK A · 2015 to 2024
$5.2M
ERBB RECEPTOR HOMO- AND HETERO- DIMERIZATIONR01CA079992 · NCI · UNIVERSITY OF PENNSYLVANIA · PI LEMMON, MARK A · 1999 to 2013
$3.7M
NCI NIH HHS R01 CA079992NCI NIH HHS R01 CA198164NIGMS NIH HHS R35 GM122485
6 · The paper itself

Abstract

Receptor tyrosine kinases (RTKs) are transmembrane receptors of great clinical interest due to their role in disease. Historically, therapeutics targeting RTKs have been identified using in vitro kinase assays. Due to frequent development of drug resistance, however, there is a need to identify more diverse compounds that inhibit mutated but not wild-type RTKs. Here, we describe MaMTH-DS (mammalian membrane two-hybrid drug screening), a live-cell platform for high-throughput identification of small molecules targeting functional protein-protein interactions of RTKs. We applied MaMTH-DS to an oncogenic epidermal growth factor receptor (EGFR) mutant resistant to the latest generation of clinically approved tyrosine kinase inhibitors (TKIs). We identified four mutant-specific compounds, including two that would not have been detected by conventional in vitro kinase assays. One of these targets mutant EGFR via a new mechanism of action, distinct from classical TKI inhibition. Our results demonstrate how MaMTH-DS is a powerful complement to traditional drug screening approaches.

Indexed as

Carcinoma, Non-Small-Cell LungCell LineCell Line, TumorDNA NucleotidyltransferasesDrug DiscoveryDrug Resistance, NeoplasmErbB ReceptorsGenes, ReporterHigh-Throughput Screening AssaysHumansLuciferasesLung NeoplasmsMutationPhosphorylationProtein Kinase InhibitorsReproducibility of ResultsDNA NucleotidyltransferasesEGFR protein, humanErbB ReceptorsFLP recombinaseLuciferasesmidostaurinProtein Kinase InhibitorsSmall Molecule LibrariesStaurosporine

Identifiers

PMID32094923
PMCPMC8123931
OpenAlexW3007674754

What OpenQuestion holds

Textmetadata
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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.