Comprehensive targeting of resistance to inhibition of RTK signaling pathways by using glucocorticoids.

A549 Cells Animals Carcinoma, Non-Small-Cell Lung Cytokines / metabolism Disease Models, Animal Drug Resistance, Neoplasm / drug effects ErbB Receptors / drug effects Female Glucocorticoids / pharmacology Humans Lung Neoplasms Mice Mice, Inbred NOD Mice, SCID Mice, Transgenic Prednisone Protein Kinase Inhibitors / pharmacology STAT3 Transcription Factor / metabolism Signal Transduction / drug effects Thalidomide Tumor Necrosis Factor Inhibitors Up-Regulation

Journal

Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555

Informations de publication

Date de publication:
01 12 2021
Historique:
received: 23 02 2021
accepted: 09 11 2021
entrez: 2 12 2021
pubmed: 3 12 2021
medline: 29 12 2021
Statut: epublish

Résumé

Inhibition of RTK pathways in cancer triggers an adaptive response that promotes therapeutic resistance. Because the adaptive response is multifaceted, the optimal approach to blunting it remains undetermined. TNF upregulation is a biologically significant response to EGFR inhibition in NSCLC. Here, we compared a specific TNF inhibitor (etanercept) to thalidomide and prednisone, two drugs that block TNF and also other inflammatory pathways. Prednisone is significantly more effective in suppressing EGFR inhibition-induced inflammatory signals. Remarkably, prednisone induces a shutdown of bypass RTK signaling and inhibits key resistance signals such as STAT3, YAP and TNF-NF-κB. Combined with EGFR inhibition, prednisone is significantly superior to etanercept or thalidomide in durably suppressing tumor growth in multiple mouse models, indicating that a broad suppression of adaptive signals is more effective than blocking a single component. We identify prednisone as a drug that can effectively inhibit adaptive resistance with acceptable toxicity in NSCLC and other cancers.

Identifiants

DOI: 10.1038/s41467-021-27276-7 PMID: 34853306 PMC: PMC8636603
pubmed: 34853306
doi: 10.1038/s41467-021-27276-7
pii: 10.1038/s41467-021-27276-7
pmc: PMC8636603
doi:

Substances chimiques

Cytokines 0
Glucocorticoids 0
Protein Kinase Inhibitors 0
STAT3 Transcription Factor 0
Stat3 protein, mouse 0
Tumor Necrosis Factor Inhibitors 0
Thalidomide 4Z8R6ORS6L
EGFR protein, mouse EC 2.7.10.1
ErbB Receptors EC 2.7.10.1
Prednisone VB0R961HZT

Types de publication

Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, Non-P.H.S.

Langues

eng

Sous-ensembles de citation

IM

Pagination

7014

Subventions

Organisme : NCI NIH HHS
ID : R01 CA197796
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA246807
Pays : United States
Organisme : NIH HHS
ID : S10 OD023552
Pays : United States
Organisme : NCI NIH HHS
ID : P30 CA142543
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA244212
Pays : United States
Organisme : NCI NIH HHS
ID : K24 CA201543
Pays : United States
Organisme : NCI NIH HHS
ID : P50 CA070907
Pays : United States
Organisme : NCI NIH HHS
ID : U01 CA176284
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA194578
Pays : United States
Organisme : BLRD VA
ID : I01 BX002559
Pays : United States

Informations de copyright

© 2021. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.

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Auteurs

Ke Gong (K)

Department of Neurology, University of Texas Southwestern Medical Center, Dallas, TX, 75390, USA.
Hubei Province Key Laboratory of Allergy and Immunology and Department of Immunology, School of Basic Medical Sciences, Wuhan University, Wuhan, 430071, China.

Gao Guo (G)

Department of Neurology, University of Texas Southwestern Medical Center, Dallas, TX, 75390, USA.

Nicole A Beckley (NA)

Department of Neurology, University of Texas Southwestern Medical Center, Dallas, TX, 75390, USA.

Xiaoyao Yang (X)

Department of Neurology, University of Texas Southwestern Medical Center, Dallas, TX, 75390, USA.

Yue Zhang (Y)

Department of Neurology, University of Texas Southwestern Medical Center, Dallas, TX, 75390, USA.

David E Gerber (DE)

Division of Hematology-Oncology, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX, 75390, USA.
Harold C. Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX, 75390, USA.
Department of Population and Data Sciences, University of Texas Southwestern Medical Center, Dallas, TX, 75390, USA.
ORCID: 0000-0002-7812-6741

John D Minna (JD)

Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, TX, 75390, USA.
Hamon Center for Therapeutic Oncology Research, University of Texas Southwestern Medical Center, Dallas, TX, 75390, USA.
ORCID: 0000-0002-7776-0767

Sandeep Burma (S)

Department of Neurosurgery, University of Texas Health San Antonio, San Antonio, TX, 78229, USA.
Biochemistry & Structural Biology, University of Texas Health San Antonio, San Antonio, TX, 78229, USA.
ORCID: 0000-0001-7057-9845

Dawen Zhao (D)

Departments of Biomedical Engineering, Wake Forest School of Medicine, Winston Salem, NC, 27157, USA.
ORCID: 0000-0001-6428-1698

Esra A Akbay (EA)

Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX, 75390, USA.
ORCID: 0000-0002-4149-2529

Amyn A Habib (AA)

Department of Neurology, University of Texas Southwestern Medical Center, Dallas, TX, 75390, USA. Amyn.Habib@UTSouthwestern.edu.
Harold C. Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX, 75390, USA. Amyn.Habib@UTSouthwestern.edu.
VA North Texas Health Care System, Dallas, TX, 75216, USA. Amyn.Habib@UTSouthwestern.edu.
ORCID: 0000-0003-4164-9028

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Classifications MeSH

questionsmedicales.fr › Cellules › Cellules épithéliales › Cellules A549 › Comprehensive targeting of resistance to...
questionsmedicales.fr › Eucaryotes › Animaux › Comprehensive targeting of resistance to...
questionsmedicales.fr › Maladies de l'appareil respiratoire › Tumeurs de l'appareil respiratoire › Tumeurs du poumon › Tumeurs des bronches › Carcinome bronchogénique › Carcinome pulmonaire non à petites cellules › Comprehensive targeting of resistance to...
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questionsmedicales.fr › Techniques d'investigation › Modèles théoriques › Modèles biologiques › Modèles animaux de maladie humaine › Comprehensive targeting of resistance to...
questionsmedicales.fr › Phénomènes physiologiques › Phénomènes pharmacologiques et toxicologiques › Phénomènes pharmacologiques › Résistance aux substances › Résistance aux médicaments antinéoplasiques › Comprehensive targeting of resistance to...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines membranaires › Récepteurs de surface cellulaire › Récepteurs peptidiques › Récepteur facteur croissance › Récepteurs ErbB › Comprehensive targeting of resistance to...
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questionsmedicales.fr › Maladies de l'appareil respiratoire › Tumeurs de l'appareil respiratoire › Tumeurs du poumon › Comprehensive targeting of resistance to...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Rodentia › Muridae › Murinae › Souris › Comprehensive targeting of resistance to...
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questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Rodentia › Muridae › Murinae › Souris › Souris transgéniques › Comprehensive targeting of resistance to...
questionsmedicales.fr › Composés polycycliques › Composés à cycles fusionnés › Stéroïdes › Prégnanes › Prégnadiènes › Prégnadiènediols › Prednisone › Comprehensive targeting of resistance to...
questionsmedicales.fr › Actions chimiques et utilisations › Actions pharmacologiques › Mécanismes moléculaires de l'action pharmacologique › Antienzymes › Inhibiteurs de protéines kinases › Comprehensive targeting of resistance to...
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