Evidence map›Paper›PMID 35108526›Full record

ArticleCell reports2022

Extensive conformational and physical plasticity protects HER2-HER3 tumorigenic signaling.

Marcia R Campbell, Ana Ruiz-Saenz, Yuntian Zhang, Elliott Peterson, Veronica Steri, Julie Oeffinger, Maryjo Sampang, Natalia Jura, Mark M Moasser

Erratum issuedAbstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Cell reports, 2022. 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 7 papers.

0numbers the graph read from it
0cells of the map it votes in
7citing papers in PubMed
–field-weighted citation impact
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

7 citing papers in PubMed.

  1. Article
  2. Review
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  6. Article
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4 · The record

Corrections and comments

5 · Who and what money

Authors and funding

9 authors.

Marcia R CampbellDepartment of Medicine, University of California, San Francisco, San Francisco, CA 94143, USA.
Ana Ruiz-SaenzDepartments of Cell Biology & Medical Oncology, Erasmus Medical Center, Rotterdam, the Netherlands.
Yuntian ZhangDepartment of Medicine, University of California, San Francisco, San Francisco, CA 94143, USA.
Elliott PetersonDepartment of Medicine, University of California, San Francisco, San Francisco, CA 94143, USA.
Veronica SteriHelen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA 94143, USA.
Julie OeffingerDepartment of Medicine, University of California, San Francisco, San Francisco, CA 94143, USA.
Maryjo SampangDepartment of Medicine, University of California, San Francisco, San Francisco, CA 94143, USA.
Natalia JuraCardiovascular Research Institute, University of California, San Francisco, San Francisco, CA 94143, USA; Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, CA 94143, USA.
Mark M MoasserDepartment of Medicine, University of California, San Francisco, San Francisco, CA 94143, USA; Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA 94143, USA. Electronic address: mark.moasser@ucsf.edu.

Funding

Understanding resistance to HER family tyrosine kinase inhibitorsR01CA122216 · NCI · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · PI MOASSER, MARK M · 2007 to 2017
$3.0M
Structural and Functional Studies of HER ReceptorsR35GM139636 · NIGMS · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · PI Natalia Jura · 2021 to 2026
$2.5M
Structural and Functional Studies of HER Receptor Tyrosine KinasesR01GM109176 · NIGMS · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · PI JURA, NATALIA · 2014 to 2018
$1.8M
NCI NIH HHS R01 CA122216NIGMS NIH HHS R01 GM109176NIGMS NIH HHS R35 GM139636
6 · The paper itself

Abstract

Surface-targeting biotherapeutic agents have been successful in treating HER2-amplified cancers through immunostimulation or chemodelivery but have failed to produce effective inhibitors of constitutive HER2-HER3 signaling. We report an extensive structure-function analysis of this tumor driver, revealing complete uncoupling of intracellular signaling and tumorigenic function from regulation or constraints from their extracellular domains (ECDs). The canonical HER3 ECD conformational changes and exposure of the dimerization interface are nonessential, and the entire ECDs of HER2 and HER3 are redundant for tumorigenic signaling. Restricting the proximation of partner ECDs with bulk and steric clash through extremely disruptive receptor engineering leaves tumorigenic signaling unperturbed. This is likely due to considerable conformational flexibilities across the span of these receptor molecules and substantial undulations in the plane of the plasma membrane, none of which had been foreseen as impediments to targeting strategies. The massive overexpression of HER2 functionally and physically uncouples intracellular signaling from extracellular constraints.

Indexed as

AnimalsAntibodies, Monoclonal, HumanizedBreast NeoplasmsCarcinogenesisCell Line, TumorCell ProliferationErb-b2 Receptor Tyrosine KinasesHumansPhosphorylationReceptor, ErbB-3Signal TransductionTrastuzumabAntibodies, Monoclonal, HumanizedERBB2 protein, humanErb-b2 Receptor Tyrosine KinasesERBB3 protein, humanReceptor, ErbB-3Trastuzumabbreast cancerERBB2ERBB3HER2HER2-HER3 dimerizationHER2 overexpressionHER3pertuzumabtrastuzumab

Identifiers

PMID35108526
PMCPMC8865943

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.