Aurora kinase A drives the evolution of resistance to third-generation EGFR inhibitors in lung cancer.

Animals Apoptosis / drug effects Aurora Kinase A / metabolism Cell Count Cell Cycle Proteins / metabolism Cell Line, Tumor Drug Resistance, Neoplasm ErbB Receptors / antagonists & inhibitors Humans Lung Neoplasms / drug therapy Mice Microtubule-Associated Proteins / metabolism Mutation / genetics Neoplasm, Residual / drug therapy Nuclear Proteins / metabolism Phosphorylation / drug effects Protein Kinase Inhibitors / pharmacology

Journal

Nature medicine
ISSN: 1546-170X
Titre abrégé: Nat Med
Pays: United States
ID NLM: 9502015

Informations de publication

Date de publication:
01 2019
Historique:
received: 13 09 2017
accepted: 04 10 2018
pubmed: 28 11 2018
medline: 11 5 2019
entrez: 28 11 2018
Statut: ppublish

Résumé

Although targeted therapies often elicit profound initial patient responses, these effects are transient due to residual disease leading to acquired resistance. How tumors transition between drug responsiveness, tolerance and resistance, especially in the absence of preexisting subclones, remains unclear. In epidermal growth factor receptor (EGFR)-mutant lung adenocarcinoma cells, we demonstrate that residual disease and acquired resistance in response to EGFR inhibitors requires Aurora kinase A (AURKA) activity. Nongenetic resistance through the activation of AURKA by its coactivator TPX2 emerges in response to chronic EGFR inhibition where it mitigates drug-induced apoptosis. Aurora kinase inhibitors suppress this adaptive survival program, increasing the magnitude and duration of EGFR inhibitor response in preclinical models. Treatment-induced activation of AURKA is associated with resistance to EGFR inhibitors in vitro, in vivo and in most individuals with EGFR-mutant lung adenocarcinoma. These findings delineate a molecular path whereby drug resistance emerges from drug-tolerant cells and unveils a synthetic lethal strategy for enhancing responses to EGFR inhibitors by suppressing AURKA-driven residual disease and acquired resistance.

Identifiants

DOI: 10.1038/s41591-018-0264-7 PMID: 30478424 PMC: PMC6324945
pubmed: 30478424
doi: 10.1038/s41591-018-0264-7
pii: 10.1038/s41591-018-0264-7
pmc: PMC6324945
mid: NIHMS1508964
doi:

Substances chimiques

Cell Cycle Proteins 0
Microtubule-Associated Proteins 0
Nuclear Proteins 0
Protein Kinase Inhibitors 0
TPX2 protein, human 0
EGFR protein, human EC 2.7.10.1
ErbB Receptors EC 2.7.10.1
Aurora Kinase A EC 2.7.11.1

Types de publication

Journal Article Research Support, N.I.H., Extramural

Langues

eng

Sous-ensembles de citation

IM

Pagination

111-118

Subventions

Organisme : NCI NIH HHS
ID : U54 CA224081
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA169338
Pays : United States
Organisme : NIGMS NIH HHS
ID : R01 GM107671
Pays : United States
Organisme : NCI NIH HHS
ID : U01 CA168370
Pays : United States
Organisme : NCI NIH HHS
ID : U01 CA217882
Pays : United States
Organisme : Doris Duke Charitable Foundation
ID : 2018110
Pays : United States

Commentaires et corrections

Type : CommentIn

Références

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Auteurs

Khyati N Shah (KN)

Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, San Francisco, CA, USA.
Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA, USA.
ORCID: 0000-0002-2510-803X

Roma Bhatt (R)

Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, San Francisco, CA, USA.
Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA, USA.

Julia Rotow (J)

Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA, USA.
Department of Medicine, University of California, San Francisco, San Francisco, CA, USA.

Julia Rohrberg (J)

Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA, USA.
Department of Medicine, University of California, San Francisco, San Francisco, CA, USA.

Victor Olivas (V)

Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA, USA.
Department of Medicine, University of California, San Francisco, San Francisco, CA, USA.

Victoria E Wang (VE)

Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA, USA.

Golzar Hemmati (G)

Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA, USA.
Department of Medicine, University of California, San Francisco, San Francisco, CA, USA.

Maria M Martins (MM)

Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA, USA.
Department of Medicine, University of California, San Francisco, San Francisco, CA, USA.

Ashley Maynard (A)

Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA, USA.
Department of Medicine, University of California, San Francisco, San Francisco, CA, USA.

Jonathan Kuhn (J)

Department of Cell and Tissue Biology, University of California, San Francisco, San Francisco, CA, USA.

Jacqueline Galeas (J)

Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA, USA.

Hayley J Donnella (HJ)

Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, San Francisco, CA, USA.
Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA, USA.
ORCID: 0000-0002-9403-0192

Swati Kaushik (S)

Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, San Francisco, CA, USA.
Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA, USA.

Angel Ku (A)

Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, San Francisco, CA, USA.
Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA, USA.

Sophie Dumont (S)

Department of Cell and Tissue Biology, University of California, San Francisco, San Francisco, CA, USA.

Gregor Krings (G)

Department of Pathology, University of California, San Francisco, San Francisco, CA, USA.

Henry J Haringsma (HJ)

Clovis Oncology, Inc., Boulder, CO, USA.

Liliane Robillard (L)

Clovis Oncology, Inc., Boulder, CO, USA.

Andrew D Simmons (AD)

Clovis Oncology, Inc., Boulder, CO, USA.

Thomas C Harding (TC)

Clovis Oncology, Inc., Boulder, CO, USA.

Frank McCormick (F)

Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA, USA.

Andrei Goga (A)

Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA, USA.
Department of Cell and Tissue Biology, University of California, San Francisco, San Francisco, CA, USA.
ORCID: 0000-0001-9127-0986

Collin M Blakely (CM)

Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA, USA.
Department of Medicine, University of California, San Francisco, San Francisco, CA, USA.

Trever G Bivona (TG)

Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA, USA.
Department of Medicine, University of California, San Francisco, San Francisco, CA, USA.
ORCID: 0000-0001-5734-4128

Sourav Bandyopadhyay (S)

Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, San Francisco, CA, USA. sourav.bandyopadhyay@ucsf.edu.
Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA, USA. sourav.bandyopadhyay@ucsf.edu.
ORCID: 0000-0003-3120-923X

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Classifications MeSH

questionsmedicales.fr › Eucaryotes › Animaux › Aurora kinase A drives the evolution of...
questionsmedicales.fr › Phénomènes physiologiques cellulaires › Mort cellulaire › Mort cellulaire régulée › Apoptose › Aurora kinase A drives the evolution of...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines et peptides de signalisation intracellulaire › Protein-Serine-Threonine Kinases › Aurora kinases › Aurora kinase A › Aurora kinase A drives the evolution of...
questionsmedicales.fr › Phénomènes physiologiques cellulaires › Numération cellulaire › Aurora kinase A drives the evolution of...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines du cycle cellulaire › Aurora kinase A drives the evolution of...
questionsmedicales.fr › Cellules › Cellules cultivées › Cellules cancéreuses en culture › Lignée cellulaire tumorale › Aurora kinase A drives the evolution of...
questionsmedicales.fr › Phénomènes physiologiques › Phénomènes pharmacologiques et toxicologiques › Phénomènes pharmacologiques › Résistance aux substances › Résistance aux médicaments antinéoplasiques › Aurora kinase A drives the evolution of...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines membranaires › Récepteurs de surface cellulaire › Récepteurs peptidiques › Récepteur facteur croissance › Récepteurs ErbB › Aurora kinase A drives the evolution of...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Primates › Haplorhini › Catarrhini › Hominidae › Humains › Aurora kinase A drives the evolution of...
questionsmedicales.fr › Maladies de l'appareil respiratoire › Tumeurs de l'appareil respiratoire › Tumeurs du poumon › Aurora kinase A drives the evolution of...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Rodentia › Muridae › Murinae › Souris › Aurora kinase A drives the evolution of...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines de tissu nerveux › Protéines associées aux microtubules › Aurora kinase A drives the evolution of...
questionsmedicales.fr › Phénomènes génétiques › Variation génétique › Mutation › Aurora kinase A drives the evolution of...
questionsmedicales.fr › États, signes et symptômes pathologiques › Processus pathologiques › Processus néoplasiques › Maladie résiduelle › Aurora kinase A drives the evolution of...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines nucléaires › Aurora kinase A drives the evolution of...
questionsmedicales.fr › Métabolisme › Phosphorylation › Aurora kinase A drives the evolution of...
questionsmedicales.fr › Actions chimiques et utilisations › Actions pharmacologiques › Mécanismes moléculaires de l'action pharmacologique › Antienzymes › Inhibiteurs de protéines kinases › Aurora kinase A drives the evolution of...