Evidence map›Paper›PMID 33888713›Full record

ArticleNature communications2021

Disruption of the HER3-PI3K-mTOR oncogenic signaling axis and PD-1 blockade as a multimodal precision immunotherapy in head and neck cancer.

Zhiyong Wang, Yusuke Goto, Michael M Allevato, Victoria H Wu, Robert Saddawi-Konefka, Mara Gilardi, Diego Alvarado, Bryan S Yung, Aoife O'Farrell, Alfredo A Molinolo and 5 more

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

Article in Nature communications, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 59 papers, 2 of them syntheses that pooled it.

0numbers the graph read from it
0cells of the map it votes in
59citing papers in PubMed, 2 pooled it
6.0field-weighted citation impact, top 2% 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

59 citing papers in PubMed, 2 syntheses or guidelines pooled it, 85 citations in OpenAlex.

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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

15 authors at 5 institutions in 1 country.

Zhiyong Wang *Moores Cancer Center, University of California San Diego, La Jolla, CA, USA.ORCID 0000-0002-3574-6078
Yusuke Goto *Moores Cancer Center, University of California San Diego, La Jolla, CA, USA.
Michael M AllevatoMoores Cancer Center, University of California San Diego, La Jolla, CA, USA.
Victoria H WuMoores Cancer Center, University of California San Diego, La Jolla, CA, USA.
Robert Saddawi-KonefkaMoores Cancer Center, University of California San Diego, La Jolla, CA, USA. rsaddawi@health.ucsd.edu.ORCID 0000-0002-9936-1695
Mara GilardiMoores Cancer Center, University of California San Diego, La Jolla, CA, USA.
Diego AlvaradoCelldex Therapeutics, Hampton, NJ, USA.
Bryan S YungMoores Cancer Center, University of California San Diego, La Jolla, CA, USA.
Aoife O'FarrellMoores Cancer Center, University of California San Diego, La Jolla, CA, USA.
Alfredo A MolinoloMoores Cancer Center, University of California San Diego, La Jolla, CA, USA.
Umamaheswar DuvvuriDepartment of Otolaryngology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
Jennifer R GrandisDepartment of Otolaryngology-Head and Neck Surgery, University of California San Francisco, San Francisco, CA, USA.
Joseph A CalifanoMoores Cancer Center, University of California San Diego, La Jolla, CA, USA.
Ezra E W CohenMoores Cancer Center, University of California San Diego, La Jolla, CA, USA.
J Silvio GutkindMoores Cancer Center, University of California San Diego, La Jolla, CA, USA. sgutkind@ucsd.edu.ORCID 0000-0002-5150-4482
University of California San Diego · USCelldex Therapeutics (United States) · USUC San Diego Health System · USUniversity of California, San Francisco · USUniversity of Pittsburgh · US

Funding

VIRAL MALIGNANCYP30CA023100 · NCI · UNIVERSITY OF CALIFORNIA, SAN DIEGO · PI DIANE M SIMEONE · 1985 to 2026
$124.9M
GRADUATE TRAINING IN CELLULAR &MOLECULAR PHARMACOLOGYT32GM007752 · NIGMS · UNIVERSITY OF CALIFORNIA, SAN DIEGO · PI BROWN, JOAN HELLER, HANDEL, TRACY M · 1985 to 2023
$13.5M
Using Networks to Seed Hierarchical Whole-cell Models of CancerU54CA209891 · NCI · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · PI ASHWORTH, ALAN · 2017 to 2021
$10.9M
Integrating genomics and the protein interactome for HPV+ head and neck cancer therapyR35CA231998 · NCI · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · PI GRANDIS, JENNIFER RUBIN · 2018 to 2024
$6.2M
PI3K Pathway Mutations in Head and Neck CancerR01DE023685 · NIDCR · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · PI GRANDIS, JENNIFER RUBIN, JOHNSON, DANIEL E · 2014 to 2023
$5.1M
Targeting Signaling Vulnerabilities for Oral Cancer PreventionR01DE026644 · NIDCR · UNIVERSITY OF CALIFORNIA, SAN DIEGO · PI Jorge Silvio Gutkind, SCOTT M LIPPMAN · 2017 to 2026
$4.7M
Stimulating Neo-Antigen Specific T Cell Responses in Head and Neck CancersU01DE028227 · NIDCR · LA JOLLA INSTITUTE FOR IMMUNOLOGY · PI GUTKIND, JORGE SILVIO, RAO, ANJANA · 2018 to 2022
$4.6M
Co-targeting the HER3 oncogenic signaling circuitry and PD-1 as a novel multimodal precision immunotherapy for HNSCCR01CA247551 · NCI · UNIVERSITY OF CALIFORNIA, SAN DIEGO · PI GUTKIND, JORGE SILVIO · 2020 to 2024
$2.5M
Signal Transduction by PI3K/mTORR01DE030497 · NIDCR · UNIVERSITY OF CALIFORNIA, SAN DIEGO · PI GUTKIND, JORGE SILVIO, ZHANG, JIN · 2021 to 2025
$2.4M
Targeting the EGFR-PI3K/mTOR Signaling Circuitry: A Network-Based Approach for Oral Cancer Precision TherapyR01DE026870 · NIDCR · UNIVERSITY OF CALIFORNIA, SAN DIEGO · PI GUTKIND, JORGE SILVIO · 2018 to 2022
$2.3M
Inhibition of lysosomal flux in carcinogen-induced head and neck cancerR01DE028343 · NIDCR · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · PI DUVVURI, UMAMAHESWAR · 2019 to 2023
$1.9M
Super-resolution confocal microscopeS10OD021831 · OD · LA JOLLA INSTITUTE FOR IMMUNOLOGY · PI LEY, KLAUS F. · 2017 to 2017
$566k
NCI NIH HHS P30 CA023100NCI NIH HHS R01 CA247551NCI NIH HHS R35 CA231998NCI NIH HHS U54 CA209891NIDCR NIH HHS F32 DE029990NIDCR NIH HHS R01 DE023685NIDCR NIH HHS R01 DE026644NIDCR NIH HHS R01 DE026870NIDCR NIH HHS R01 DE028343NIDCR NIH HHS R01 DE030497NIDCR NIH HHS U01 DE028227NIGMS NIH HHS T32 GM007752NIH HHS S10 OD021831
6 · The paper itself

Abstract

Immune checkpoint blockade (ICB) therapy has revolutionized head and neck squamous cell carcinoma (HNSCC) treatment, but <20% of patients achieve durable responses. Persistent activation of the PI3K/AKT/mTOR signaling circuitry represents a key oncogenic driver in HNSCC; however, the potential immunosuppressive effects of PI3K/AKT/mTOR inhibitors may limit the benefit of their combination with ICB. Here we employ an unbiased kinome-wide siRNA screen to reveal that HER3, is essential for the proliferation of most HNSCC cells that do not harbor PIK3CA mutations. Indeed, we find that persistent tyrosine phosphorylation of HER3 and PI3K recruitment underlies aberrant PI3K/AKT/mTOR signaling in PIK3CA wild type HNSCCs. Remarkably, antibody-mediated HER3 blockade exerts a potent anti-tumor effect by suppressing HER3-PI3K-AKT-mTOR oncogenic signaling and concomitantly reversing the immune suppressive tumor microenvironment. Ultimately, we show that HER3 inhibition and PD-1 blockade may provide a multimodal precision immunotherapeutic approach for PIK3CA wild type HNSCC, aimed at achieving durable cancer remission.

Indexed as

AnimalsAntineoplastic Combined Chemotherapy ProtocolsCell Line, TumorCell ProliferationClass I Phosphatidylinositol 3-KinasesFemaleHead and Neck NeoplasmsHumansImmune Checkpoint InhibitorsImmunotherapyMiceMutationPrecision MedicineProgrammed Cell Death 1 ReceptorProtein Kinase InhibitorsReceptor, ErbB-3Class I Phosphatidylinositol 3-KinasesERBB3 protein, humanImmune Checkpoint InhibitorsMTOR protein, humanPDCD1 protein, humanPIK3CA protein, humanProgrammed Cell Death 1 ReceptorProtein Kinase InhibitorsReceptor, ErbB-3TOR Serine-Threonine Kinases

Identifiers

PMID33888713
PMCPMC8062674
OpenAlexW3153740078

What OpenQuestion holds

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LicenceCC BY
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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.