Evidence map›Paper›PMID 34857952›Full record

ArticleNature genetics2021

Paralog knockout profiling identifies DUSP4 and DUSP6 as a digenic dependence in MAPK pathway-driven cancers.

Takahiro Ito, Michael J Young, Ruitong Li, Sidharth Jain, Andreas Wernitznig, John M Krill-Burger, Christopher T Lemke, Davide Monducci, Diego J Rodriguez, Liang Chang and 12 more

Abstract read
PubMed Publisher
In one paragraph

Article in Nature genetics, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 105 papers, 1 of them a synthesis that pooled it.

0numbers the graph read from it
0cells of the map it votes in
105citing papers in PubMed, 1 pooled it
14.5field-weighted citation impact, top 1% 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

105 citing papers in PubMed, 1 synthesis or guideline pooled it, 167 citations in OpenAlex.

  1. Pooled it
  2. Review
  3. Article
  4. DUSP4 promotes anti-tumor CD8Nature communications · 2026
    Article
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  6. Article
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  14. Variable thresholds for phosphorylation targets of the ERK signaling pathway.Proceedings of the National Academy of Sciences of the United States of America · 2026
    Article
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45 more citing papers are in PubMed but not listed here.

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

22 authors at 2 institutions in 2 countries.

Takahiro ItoBroad Institute of Harvard and MIT, Cambridge, MA, USA.
Michael J YoungBroad Institute of Harvard and MIT, Cambridge, MA, USA.ORCID http://orcid.org/0000-0002-9167-2413
Ruitong LiBroad Institute of Harvard and MIT, Cambridge, MA, USA.
Sidharth JainBroad Institute of Harvard and MIT, Cambridge, MA, USA.ORCID http://orcid.org/0000-0002-6263-651X
Andreas WernitznigBroad Institute of Harvard and MIT, Cambridge, MA, USA.
John M Krill-BurgerBroad Institute of Harvard and MIT, Cambridge, MA, USA.ORCID http://orcid.org/0000-0001-9614-4671
Christopher T LemkeBroad Institute of Harvard and MIT, Cambridge, MA, USA.
Davide MonducciBroad Institute of Harvard and MIT, Cambridge, MA, USA.ORCID http://orcid.org/0000-0002-6761-1207
Diego J RodriguezBroad Institute of Harvard and MIT, Cambridge, MA, USA.ORCID http://orcid.org/0000-0002-0053-8674
Liang ChangBroad Institute of Harvard and MIT, Cambridge, MA, USA.
Sanjukta DuttaBroad Institute of Harvard and MIT, Cambridge, MA, USA.ORCID http://orcid.org/0000-0002-8880-2192
Debjani PalBroad Institute of Harvard and MIT, Cambridge, MA, USA.ORCID http://orcid.org/0000-0002-3030-2590
Brenton R PaolellaBroad Institute of Harvard and MIT, Cambridge, MA, USA.ORCID http://orcid.org/0000-0003-3394-828X
Michael V RothbergBroad Institute of Harvard and MIT, Cambridge, MA, USA.
David E RootBroad Institute of Harvard and MIT, Cambridge, MA, USA.ORCID http://orcid.org/0000-0001-5122-861X
Cory M JohannessenBroad Institute of Harvard and MIT, Cambridge, MA, USA.ORCID http://orcid.org/0000-0002-2618-1036
Laxmi ParidaIBM Research, T.J. Watson Research Center, Yorktown Heights, NY, USA.ORCID http://orcid.org/0000-0002-7872-5074
Gad GetzBroad Institute of Harvard and MIT, Cambridge, MA, USA.ORCID http://orcid.org/0000-0002-0936-0753
Francisca VazquezBroad Institute of Harvard and MIT, Cambridge, MA, USA.ORCID http://orcid.org/0000-0002-2857-4685
John G DoenchBroad Institute of Harvard and MIT, Cambridge, MA, USA.ORCID http://orcid.org/0000-0002-3707-9889
Mahdi ZamanighomiBroad Institute of Harvard and MIT, Cambridge, MA, USA.
William R SellersBroad Institute of Harvard and MIT, Cambridge, MA, USA. wsellers@broadinstitute.org.ORCID http://orcid.org/0000-0002-3539-9803
Broad Institute · USIBM Research - Thomas J. Watson Research Center · US

Funding

No grant is acknowledged in the PubMed record.

6 · The paper itself

Abstract

Although single-gene perturbation screens have revealed a number of new targets, vulnerabilities specific to frequently altered drivers have not been uncovered. An important question is whether the compensatory relationship between functionally redundant genes masks potential therapeutic targets in single-gene perturbation studies. To identify digenic dependencies, we developed a CRISPR paralog targeting library to investigate the viability effects of disrupting 3,284 genes, 5,065 paralog pairs and 815 paralog families. We identified that dual inactivation of DUSP4 and DUSP6 selectively impairs growth in NRAS and BRAF mutant cells through the hyperactivation of MAPK signaling. Furthermore, cells resistant to MAPK pathway therapeutics become cross-sensitized to DUSP4 and DUSP6 perturbations such that the mechanisms of resistance to the inhibitors reinforce this mechanism of vulnerability. Together, multigene perturbation technologies unveil previously unrecognized digenic vulnerabilities that may be leveraged as new therapeutic targets in cancer.

Indexed as

MAP Kinase Signaling SystemCell Line, TumorClustered Regularly Interspaced Short Palindromic RepeatsDual Specificity Phosphatase 6Dual-Specificity PhosphatasesEnzyme ActivationGene Knockout TechniquesGTP PhosphohydrolasesHumansMelanoma, ExperimentalMembrane ProteinsMitogen-Activated Protein Kinase PhosphatasesNeoplasmsProto-Oncogene Proteins B-rafDual Specificity Phosphatase 6Dual-Specificity PhosphatasesDUSP4 protein, humanDUSP6 protein, humanGTP PhosphohydrolasesMembrane ProteinsMitogen-Activated Protein Kinase PhosphatasesNRAS protein, humanProto-Oncogene Proteins B-raf

Identifiers

PMID34857952
OpenAlexW3217729113

What OpenQuestion holds

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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.