Evidence map›Paper›PMID 33326793›Full record

ArticleCell reports2020

Synthetic Lethal Interaction between the ESCRT Paralog Enzymes VPS4A and VPS4B in Cancers Harboring Loss of Chromosome 18q or 16q.

Jasper E Neggers, Brenton R Paolella, Adhana Asfaw, Michael V Rothberg, Thomas A Skipper, Annan Yang, Radha L Kalekar, John M Krill-Burger, Neekesh V Dharia, Guillaume Kugener and 21 more

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

Article in Cell reports, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. An erratum has been issued. Cited by 45 papers.

0numbers the graph read from it
0cells of the map it votes in
45citing papers in PubMed
3.1field-weighted citation impact, top 8% 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

45 citing papers in PubMed, 58 citations in OpenAlex.

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  9. ESCRT-III function in membrane fission and repair.Nature reviews. Molecular cell biology · 2026
    Review
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4 · The record

Corrections and comments

5 · Who and what money

Authors and funding

31 authors at 2 institutions in 1 country.

Jasper E NeggersCancer Program, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA.
Brenton R PaolellaCancer Program, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA.
Adhana AsfawCancer Program, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
Michael V RothbergCancer Program, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
Thomas A SkipperCancer Program, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
Annan YangDepartment of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA.
Radha L KalekarCancer Program, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA.
John M Krill-BurgerCancer Program, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
Neekesh V DhariaCancer Program, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA; Cancer and Blood Disorders Center, Boston Children's Hospital, Harvard Medical School, Boston, MA 02215, USA.
Guillaume KugenerCancer Program, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
Jérémie KalfonCancer Program, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
Chen YuanDepartment of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA.
Nancy DumontCancer Program, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
Alfredo GonzalezCancer Program, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
Mai AbdusamadCancer Program, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
Yvonne Y LiCancer Program, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA.
Liam F SpurrCancer Program, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA.
Westley W WuCancer Program, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA.
Adam D DurbinCancer Program, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA; Cancer and Blood Disorders Center, Boston Children's Hospital, Harvard Medical School, Boston, MA 02215, USA.
Brian M WolpinDepartment of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA.
Federica PiccioniGenetic Perturbation Platform, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
David E RootGenetic Perturbation Platform, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
Jesse S BoehmCancer Program, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
Andrew D CherniackCancer Program, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA.
Aviad TsherniakCancer Program, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
Andrew L HongCancer Program, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA; Cancer and Blood Disorders Center, Boston Children's Hospital, Harvard Medical School, Boston, MA 02215, USA.
William C HahnCancer Program, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA.
Kimberly StegmaierCancer Program, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA; Cancer and Blood Disorders Center, Boston Children's Hospital, Harvard Medical School, Boston, MA 02215, USA.
Todd R GolubCancer Program, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA.
Francisca VazquezCancer Program, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA. Electronic address: vazquez@broadinstitute.org.
Andrew J AguirreCancer Program, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA. Electronic address: andrew_aguirre@dfci.harvard.edu.
Broad Institute · USHarvard University · US

Funding

Tissue and Pathology ResourcesP50CA127003 · NCI · DANA-FARBER CANCER INST · PI EL-BARDEESY, NABEEL, SELLERS, WILLIAM R · 2007 to 2023
$33.2M
The Dana-Farber Cancer Institute Cancer Target Discovery and Development CenterU01CA176058 · NCI · DANA-FARBER CANCER INST · PI HAHN, WILLIAM C. · 2013 to 2021
$7.8M
Integrating Transforming Approaches to Identify and Target New Vulnerabilities in CancerR35CA210030 · NCI · DANA-FARBER CANCER INST · PI STEGMAIER, KIMBERLY · 2016 to 2022
$7.3M
Systematic interrogation of the pancreatic cancer microenvironment in patient-derived specimensU01CA224146 · NCI · DANA-FARBER CANCER INST · PI HAHN, WILLIAM C. · 2017 to 2021
$3.0M
Functional interrogation of epigenetic vulnerabilities in KRAS-mutant pancreatic cancerK08CA218420 · NCI · DANA-FARBER CANCER INST · PI AGUIRRE, ANDREW JAMES · 2017 to 2021
$886k
NCI NIH HHS K08 CA218420NCI NIH HHS P50 CA127003NCI NIH HHS R35 CA210030NCI NIH HHS U01 CA176058NCI NIH HHS U01 CA224146
6 · The paper itself

Abstract

Few therapies target the loss of tumor suppressor genes in cancer. We examine CRISPR-SpCas9 and RNA-interference loss-of-function screens to identify new therapeutic targets associated with genomic loss of tumor suppressor genes. The endosomal sorting complexes required for transport (ESCRT) ATPases VPS4A and VPS4B score as strong synthetic lethal dependencies. VPS4A is essential in cancers harboring loss of VPS4B adjacent to SMAD4 on chromosome 18q and VPS4B is required in tumors with co-deletion of VPS4A and CDH1 (E-cadherin) on chromosome 16q. We demonstrate that more than 30% of cancers selectively require VPS4A or VPS4B. VPS4A suppression in VPS4B-deficient cells selectively leads to ESCRT-III filament accumulation, cytokinesis defects, nuclear deformation, G2/M arrest, apoptosis, and potent tumor regression. CRISPR-SpCas9 screening and integrative genomic analysis reveal other ESCRT members, regulators of abscission, and interferon signaling as modifiers of VPS4A dependency. We describe a compendium of synthetic lethal vulnerabilities and nominate VPS4A and VPS4B as high-priority therapeutic targets for cancers with 18q or 16q loss.

Indexed as

ATPases Associated with Diverse Cellular ActivitiesCell Line, TumorEndosomal Sorting Complexes Required for TransportHumansNeoplasmsVacuolar Proton-Translocating ATPasesATPases Associated with Diverse Cellular ActivitiesEndosomal Sorting Complexes Required for TransportVacuolar Proton-Translocating ATPasesVPS4A protein, humanVPS4B protein, human16q loss18q losscancerdrug targetESCRTfunctional genomicssynthetic lethalitytarget identificationVPS4AVPS4B

Identifiers

PMID33326793
PMCPMC8374858
OpenAlexW3111392704

What OpenQuestion holds

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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.