Torin2 Exploits Replication and Checkpoint Vulnerabilities to Cause Death of PI3K-Activated Triple-Negative Breast Cancer Cells.

Apoptosis / drug effects Cell Proliferation / drug effects Female Humans Naphthyridines / pharmacology Phosphatidylinositol 3-Kinases / metabolism Phosphoinositide-3 Kinase Inhibitors / pharmacology Proto-Oncogene Proteins c-akt / antagonists & inhibitors Signal Transduction TOR Serine-Threonine Kinases / antagonists & inhibitors Triple Negative Breast Neoplasms / drug therapy
ATR/Chk1 PI3K/AKT/mTOR Torin2 cell cycle mitotic catastrophe polypharmacology replication catastrophe replication stress small molecule drugs triple-negative breast cancer

Journal

Cell systems
ISSN: 2405-4720
Titre abrégé: Cell Syst
Pays: United States
ID NLM: 101656080

Informations de publication

Date de publication:
22 01 2020
Historique:
received: 11 10 2018
revised: 11 07 2019
accepted: 04 11 2019
pubmed: 10 12 2019
medline: 9 6 2021
entrez: 9 12 2019
Statut: ppublish

Résumé

Frequent mutation of PI3K/AKT/mTOR signaling pathway genes in human cancers has stimulated large investments in targeted drugs but clinical successes are rare. As a result, many cancers with high PI3K pathway activity, such as triple-negative breast cancer (TNBC), are treated primarily with chemotherapy. By systematically analyzing responses of TNBC cells to a diverse collection of PI3K pathway inhibitors, we find that one drug, Torin2, is unusually effective because it inhibits both mTOR and other PI3K-like kinases (PIKKs). In contrast to mTOR-selective inhibitors, Torin2 exploits dependencies on several kinases for S-phase progression and cell-cycle checkpoints, thereby causing accumulation of single-stranded DNA and death by replication catastrophe or mitotic failure. Thus, Torin2 and its chemical analogs represent a mechanistically distinct class of PI3K pathway inhibitors that are uniquely cytotoxic to TNBC cells. This insight could be translated therapeutically by further developing Torin2 analogs or combinations of existing mTOR and PIKK inhibitors.

Identifiants

DOI: 10.1016/j.cels.2019.11.001 PMID: 31812693 PMC: PMC7000271
pubmed: 31812693
pii: S2405-4712(19)30387-4
doi: 10.1016/j.cels.2019.11.001
pmc: PMC7000271
mid: NIHMS1546605
pii:
doi:

Substances chimiques

9-(6-aminopyridin-3-yl)-1-(3-(trifluoromethyl)phenyl)benzo(h)(1,6)naphthyridin-2(1H)-one 0
Naphthyridines 0
Phosphoinositide-3 Kinase Inhibitors 0
MTOR protein, human EC 2.7.1.1
Proto-Oncogene Proteins c-akt EC 2.7.11.1
TOR Serine-Threonine Kinases EC 2.7.11.1

Types de publication

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

Langues

eng

Sous-ensembles de citation

IM

Pagination

66-81.e11

Subventions

Organisme : NCI NIH HHS
ID : U54 CA225088
Pays : United States
Organisme : NCI NIH HHS
ID : P01 CA120964
Pays : United States
Organisme : NCI NIH HHS
ID : T32 CA009172
Pays : United States
Organisme : NHLBI NIH HHS
ID : U54 HL127365
Pays : United States
Organisme : NCI NIH HHS
ID : P30 CA006516
Pays : United States

Informations de copyright

Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.

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Auteurs

Sameer S Chopra (SS)

Laboratory of Systems Pharmacology, Harvard Medical School, 200 Longwood Avenue, Boston, MA 02115, USA; Harvard Ludwig Center, Harvard Medical School, 200 Longwood Avenue, Boston, MA 02115, USA; Dana-Farber Cancer Institute, 450 Brookline Ave, Boston, MA 02215, USA.

Anne Jenney (A)

Laboratory of Systems Pharmacology, Harvard Medical School, 200 Longwood Avenue, Boston, MA 02115, USA; Harvard Ludwig Center, Harvard Medical School, 200 Longwood Avenue, Boston, MA 02115, USA.

Adam Palmer (A)

Laboratory of Systems Pharmacology, Harvard Medical School, 200 Longwood Avenue, Boston, MA 02115, USA; Harvard Ludwig Center, Harvard Medical School, 200 Longwood Avenue, Boston, MA 02115, USA.

Mario Niepel (M)

Laboratory of Systems Pharmacology, Harvard Medical School, 200 Longwood Avenue, Boston, MA 02115, USA; Harvard Ludwig Center, Harvard Medical School, 200 Longwood Avenue, Boston, MA 02115, USA.

Mirra Chung (M)

Laboratory of Systems Pharmacology, Harvard Medical School, 200 Longwood Avenue, Boston, MA 02115, USA; Harvard Ludwig Center, Harvard Medical School, 200 Longwood Avenue, Boston, MA 02115, USA.

Caitlin Mills (C)

Laboratory of Systems Pharmacology, Harvard Medical School, 200 Longwood Avenue, Boston, MA 02115, USA; Harvard Ludwig Center, Harvard Medical School, 200 Longwood Avenue, Boston, MA 02115, USA.

Sindhu Carmen Sivakumaren (SC)

Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, 200 Longwood Avenue, Boston, MA 02115, USA; Dana-Farber Cancer Institute, 450 Brookline Ave, Boston, MA 02215, USA.

Qingsong Liu (Q)

Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, 200 Longwood Avenue, Boston, MA 02115, USA; Dana-Farber Cancer Institute, 450 Brookline Ave, Boston, MA 02215, USA.

Jia-Yun Chen (JY)

Laboratory of Systems Pharmacology, Harvard Medical School, 200 Longwood Avenue, Boston, MA 02115, USA.

Clarence Yapp (C)

Laboratory of Systems Pharmacology, Harvard Medical School, 200 Longwood Avenue, Boston, MA 02115, USA; Harvard Ludwig Center, Harvard Medical School, 200 Longwood Avenue, Boston, MA 02115, USA.

John M Asara (JM)

Division of Signal Transduction, Beth Israel Deaconess Medical Center, Harvard Medical School, 200 Longwood Avenue, Boston, MA 02115, USA.

Nathanael S Gray (NS)

Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, 200 Longwood Avenue, Boston, MA 02115, USA; Dana-Farber Cancer Institute, 450 Brookline Ave, Boston, MA 02215, USA.

Peter K Sorger (PK)

Laboratory of Systems Pharmacology, Harvard Medical School, 200 Longwood Avenue, Boston, MA 02115, USA; Harvard Ludwig Center, Harvard Medical School, 200 Longwood Avenue, Boston, MA 02115, USA. Electronic address: peter_sorger@hms.harvard.edu.

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Classifications MeSH

questionsmedicales.fr › Phénomènes physiologiques cellulaires › Mort cellulaire › Mort cellulaire régulée › Apoptose › Torin2 Exploits Replication and Checkpoint...
questionsmedicales.fr › Phénomènes physiologiques › Croissance et développement › Croissance › Processus de croissance cellulaire › Prolifération cellulaire › Torin2 Exploits Replication and Checkpoint...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Primates › Haplorhini › Catarrhini › Hominidae › Humains › Torin2 Exploits Replication and Checkpoint...
questionsmedicales.fr › Composés hétérocycliques › Composés hétérocycliques à cycles fusionnés › Composés hétérobicycliques › Naphtyridines › Torin2 Exploits Replication and Checkpoint...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines et peptides de signalisation intracellulaire › Phosphatidylinositol 3-kinases › Torin2 Exploits Replication and Checkpoint...
questionsmedicales.fr › Actions chimiques et utilisations › Actions pharmacologiques › Mécanismes moléculaires de l'action pharmacologique › Antienzymes › Inhibiteurs des phosphoinositide-3 kinases › Torin2 Exploits Replication and Checkpoint...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines tumorales › Protéines oncogènes › Protéines proto-oncogènes › Protéines proto-oncogènes c-akt › Torin2 Exploits Replication and Checkpoint...
questionsmedicales.fr › Phénomènes physiologiques cellulaires › Transduction du signal › Torin2 Exploits Replication and Checkpoint...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines et peptides de signalisation intracellulaire › Protein-Serine-Threonine Kinases › Sérine-thréonine kinases TOR › Torin2 Exploits Replication and Checkpoint...
questionsmedicales.fr › Maladies de la peau et du tissu conjonctif › Maladies de la peau › Maladies du sein › Tumeurs du sein › Tumeurs du sein triple-négatives › Torin2 Exploits Replication and Checkpoint...