Acquired resistance to combined BET and CDK4/6 inhibition in triple-negative breast cancer.

Animals Azepines / pharmacology Cell Cycle Checkpoints / drug effects Cell Proliferation / drug effects Clone Cells Cyclin-Dependent Kinase 4 / antagonists & inhibitors Cyclin-Dependent Kinase 6 / antagonists & inhibitors DNA, Neoplasm / metabolism Drug Resistance, Neoplasm / drug effects Drug Synergism Female Gene Expression Regulation, Neoplastic / drug effects Mice Models, Biological Mutation / genetics Paclitaxel / pharmacology Piperazines / pharmacology Ploidies Proteins / antagonists & inhibitors Pyridines / pharmacology Retinoblastoma Protein / genetics Treatment Outcome Triazoles / pharmacology Triple Negative Breast Neoplasms / drug therapy Up-Regulation / drug effects

Journal

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

Informations de publication

Date de publication:
11 05 2020
Historique:
received: 24 10 2019
accepted: 20 04 2020
entrez: 13 5 2020
pubmed: 13 5 2020
medline: 6 8 2020
Statut: epublish

Résumé

BET inhibitors are promising therapeutic agents for the treatment of triple-negative breast cancer (TNBC), but the rapid emergence of resistance necessitates investigation of combination therapies and their effects on tumor evolution. Here, we show that palbociclib, a CDK4/6 inhibitor, and paclitaxel, a microtubule inhibitor, synergize with the BET inhibitor JQ1 in TNBC lines. High-complexity DNA barcoding and mathematical modeling indicate a high rate of de novo acquired resistance to these drugs relative to pre-existing resistance. We demonstrate that the combination of JQ1 and palbociclib induces cell division errors, which can increase the chance of developing aneuploidy. Characterizing acquired resistance to combination treatment at a single cell level shows heterogeneous mechanisms including activation of G1-S and senescence pathways. Our results establish a rationale for further investigation of combined BET and CDK4/6 inhibition in TNBC and suggest novel mechanisms of action for these drugs and new vulnerabilities in cells after emergence of resistance.

Identifiants

DOI: 10.1038/s41467-020-16170-3 PMID: 32393766 PMC: PMC7214447
pubmed: 32393766
doi: 10.1038/s41467-020-16170-3
pii: 10.1038/s41467-020-16170-3
pmc: PMC7214447
doi:

Substances chimiques

(+)-JQ1 compound 0
Azepines 0
DNA, Neoplasm 0
Piperazines 0
Proteins 0
Pyridines 0
Retinoblastoma Protein 0
Triazoles 0
bromodomain and extra-terminal domain protein, human 0
Cyclin-Dependent Kinase 4 EC 2.7.11.22
Cyclin-Dependent Kinase 6 EC 2.7.11.22
palbociclib G9ZF61LE7G
Paclitaxel P88XT4IS4D

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

2350

Subventions

Organisme : NCI NIH HHS
ID : R35 CA197623
Pays : United States
Organisme : NCI NIH HHS
ID : P01 CA080111
Pays : United States
Organisme : NCI NIH HHS
ID : F30 CA228208
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA213404
Pays : United States
Organisme : NCI NIH HHS
ID : U54 CA193461
Pays : United States
Organisme : NCI NIH HHS
ID : P50 CA168504
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA202634
Pays : United States

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Auteurs

Jennifer Y Ge (JY)

Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, 02215, USA.
Department of Data Sciences, Dana-Farber Cancer Institute, Boston, MA, 02215, USA.
Harvard-MIT Division of Health Sciences and Technology, Harvard Medical School, Boston, MA, 02115, USA.
ORCID: 0000-0003-2933-5261

Shaokun Shu (S)

Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, 02215, USA.
Department of Medicine, Harvard Medical School, Boston, MA, 02115, USA.
Peking University Cancer Hospital and Institute, Beijing, 100142, China.

Mijung Kwon (M)

Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA, 02215, USA.
Department of Cell Biology, Harvard Medical School, Boston, MA, 02115, USA.
Department of Life Science and the Research Center for Cellular Homeostasis, Ewha Womans University, Seoul, 120-750, Korea.

Bojana Jovanović (B)

Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, 02215, USA.
Department of Medicine, Harvard Medical School, Boston, MA, 02115, USA.
Eli and Edythe L. Broad Institute, Cambridge, MA, 02142, USA.

Katherine Murphy (K)

Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, 02215, USA.

Anushree Gulvady (A)

Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, 02215, USA.
Department of Medicine, Harvard Medical School, Boston, MA, 02115, USA.
ORCID: 0000-0002-5451-9380

Anne Fassl (A)

Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, 02215, USA.
Department of Genetics, Harvard Medical School, Boston, MA, 02115, USA.

Anne Trinh (A)

Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, 02215, USA.
Department of Medicine, Harvard Medical School, Boston, MA, 02115, USA.

Yanan Kuang (Y)

Belfer Center for Applied Cancer Science, Dana-Farber Cancer Institute, Boston, MA, 02215, USA.

Grace A Heavey (GA)

Belfer Center for Applied Cancer Science, Dana-Farber Cancer Institute, Boston, MA, 02215, USA.

Adrienne Luoma (A)

Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA, 02215, USA.
Department of Microbiology and Immunobiology, Harvard Medical School, Boston, MA, 02115, USA.

Cloud Paweletz (C)

Belfer Center for Applied Cancer Science, Dana-Farber Cancer Institute, Boston, MA, 02215, USA.

Aaron R Thorner (AR)

Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, 02215, USA.
Center for Cancer Genome Discovery, Dana-Farber Cancer Institute, Boston, MA, 02215, USA.

Kai W Wucherpfennig (KW)

Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA, 02215, USA.
Department of Microbiology and Immunobiology, Harvard Medical School, Boston, MA, 02115, USA.
Ludwig Center at Harvard, Harvard Medical School, Boston, MA, 02115, USA.

Jun Qi (J)

Department of Medicine, Harvard Medical School, Boston, MA, 02115, USA.
Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, 02215, USA.

Myles Brown (M)

Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, 02215, USA.
Department of Medicine, Harvard Medical School, Boston, MA, 02115, USA.
Ludwig Center at Harvard, Harvard Medical School, Boston, MA, 02115, USA.
Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, MA, 02215, USA.

Piotr Sicinski (P)

Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, 02215, USA.
Department of Genetics, Harvard Medical School, Boston, MA, 02115, USA.
ORCID: 0000-0002-8859-5234

Thomas O McDonald (TO)

Department of Data Sciences, Dana-Farber Cancer Institute, Boston, MA, 02215, USA.
Center for Cancer Evolution, Dana-Farber Cancer Institute, Boston, MA, 02215, USA.
Department of Biostatistics, Harvard T. H. Chan School of Public Health, Boston, MA, 02115, USA.
Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA, 02138, USA.

David Pellman (D)

Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA, 02215, USA.
Department of Cell Biology, Harvard Medical School, Boston, MA, 02115, USA.
Ludwig Center at Harvard, Harvard Medical School, Boston, MA, 02115, USA.
Center for Cancer Evolution, Dana-Farber Cancer Institute, Boston, MA, 02215, USA.
Department of Pediatrics, Harvard Medical School, Boston, MA, 02115, USA.

Franziska Michor (F)

Department of Data Sciences, Dana-Farber Cancer Institute, Boston, MA, 02215, USA. michor@jimmy.harvard.edu.
Eli and Edythe L. Broad Institute, Cambridge, MA, 02142, USA. michor@jimmy.harvard.edu.
Ludwig Center at Harvard, Harvard Medical School, Boston, MA, 02115, USA. michor@jimmy.harvard.edu.
Center for Cancer Evolution, Dana-Farber Cancer Institute, Boston, MA, 02215, USA. michor@jimmy.harvard.edu.
Department of Biostatistics, Harvard T. H. Chan School of Public Health, Boston, MA, 02115, USA. michor@jimmy.harvard.edu.
Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA, 02138, USA. michor@jimmy.harvard.edu.
ORCID: 0000-0003-4869-8842

Kornelia Polyak (K)

Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, 02215, USA. kornelia_polyak@dfci.harvard.edu.
Department of Medicine, Harvard Medical School, Boston, MA, 02115, USA. kornelia_polyak@dfci.harvard.edu.
Eli and Edythe L. Broad Institute, Cambridge, MA, 02142, USA. kornelia_polyak@dfci.harvard.edu.
Ludwig Center at Harvard, Harvard Medical School, Boston, MA, 02115, USA. kornelia_polyak@dfci.harvard.edu.
Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, MA, 02215, USA. kornelia_polyak@dfci.harvard.edu.
Center for Cancer Evolution, Dana-Farber Cancer Institute, Boston, MA, 02215, USA. kornelia_polyak@dfci.harvard.edu.
ORCID: 0000-0002-5964-0382

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Classifications MeSH

questionsmedicales.fr › Eucaryotes › Animaux › Acquired resistance to combined BET and CDK4/6...
questionsmedicales.fr › Composés hétérocycliques › Composés hétéromonocycliques › Azépines › Acquired resistance to combined BET and CDK4/6...
questionsmedicales.fr › Phénomènes physiologiques cellulaires › Cycle cellulaire › Points de contrôle du cycle cellulaire › Acquired resistance to combined BET and CDK4/6...
questionsmedicales.fr › Phénomènes physiologiques › Croissance et développement › Croissance › Processus de croissance cellulaire › Prolifération cellulaire › Acquired resistance to combined BET and CDK4/6...
questionsmedicales.fr › Cellules › Cellules cultivées › Clones cellulaires › Acquired resistance to combined BET and CDK4/6...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines et peptides de signalisation intracellulaire › Protein-Serine-Threonine Kinases › Proline-directed protein kinases › Kinases cyclines-dépendantes › Kinase-4 cycline-dépendante › Acquired resistance to combined BET and CDK4/6...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines et peptides de signalisation intracellulaire › Protein-Serine-Threonine Kinases › Proline-directed protein kinases › Kinases cyclines-dépendantes › Kinase-6 cycline-dépendante › Acquired resistance to combined BET and CDK4/6...
questionsmedicales.fr › Acides nucléiques, nucléotides et nucléosides › Acides nucléiques › ADN › ADN tumoral › Acquired resistance to combined BET and CDK4/6...
questionsmedicales.fr › Phénomènes physiologiques › Phénomènes pharmacologiques et toxicologiques › Phénomènes pharmacologiques › Résistance aux substances › Résistance aux médicaments antinéoplasiques › Acquired resistance to combined BET and CDK4/6...
questionsmedicales.fr › Phénomènes physiologiques › Phénomènes pharmacologiques et toxicologiques › Phénomènes pharmacologiques › Interactions médicamenteuses › Synergie des médicaments › Acquired resistance to combined BET and CDK4/6...
questionsmedicales.fr › Phénomènes génétiques › Régulation de l'expression des gènes › Régulation de l'expression des gènes tumoraux › Acquired resistance to combined BET and CDK4/6...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Rodentia › Muridae › Murinae › Souris › Acquired resistance to combined BET and CDK4/6...
questionsmedicales.fr › Techniques d'investigation › Modèles théoriques › Modèles biologiques › Acquired resistance to combined BET and CDK4/6...
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