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Differentiation-state plasticity is a targetable resistance mechanism in basal-like breast cancer.
- Source :
-
Nature communications [Nat Commun] 2018 Sep 19; Vol. 9 (1), pp. 3815. Date of Electronic Publication: 2018 Sep 19. - Publication Year :
- 2018
-
Abstract
- Intratumoral heterogeneity in cancers arises from genomic instability and epigenomic plasticity and is associated with resistance to cytotoxic and targeted therapies. We show here that cell-state heterogeneity, defined by differentiation-state marker expression, is high in triple-negative and basal-like breast cancer subtypes, and that drug tolerant persister (DTP) cell populations with altered marker expression emerge during treatment with a wide range of pathway-targeted therapeutic compounds. We show that MEK and PI3K/mTOR inhibitor-driven DTP states arise through distinct cell-state transitions rather than by Darwinian selection of preexisting subpopulations, and that these transitions involve dynamic remodeling of open chromatin architecture. Increased activity of many chromatin modifier enzymes, including BRD4, is observed in DTP cells. Co-treatment with the PI3K/mTOR inhibitor BEZ235 and the BET inhibitor JQ1 prevents changes to the open chromatin architecture, inhibits the acquisition of a DTP state, and results in robust cell death in vitro and xenograft regression in vivo.
- Subjects :
- Animals
Antineoplastic Agents therapeutic use
Azepines pharmacology
Breast Neoplasms drug therapy
Cell Line, Tumor
Chromatin metabolism
Female
Humans
Mice, Inbred NOD
Mice, SCID
Molecular Targeted Therapy
Triazoles pharmacology
Triple Negative Breast Neoplasms pathology
Breast Neoplasms pathology
Cell Differentiation
Cell Plasticity
Drug Resistance, Neoplasm
Subjects
Details
- Language :
- English
- ISSN :
- 2041-1723
- Volume :
- 9
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- Nature communications
- Publication Type :
- Academic Journal
- Accession number :
- 30232459
- Full Text :
- https://doi.org/10.1038/s41467-018-05729-w