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Nat Commun. 2018 Sep 19;9(1):3815. doi: 10.1038/s41467-018-05729-w.

Differentiation-state plasticity is a targetable resistance mechanism in basal-like breast cancer.

Author information

1
Department of Molecular and Medical Genetics, Oregon Health & Science University, 3181 SW Sam Jackson Park Road L103, Portland, OR, 97239, USA.
2
Department of Electrical Engineering and Computer Sciences, University of California at Berkeley, 253 Cory Hall #1770, Berkeley, CA, 24720, USA.
3
Misvik Biology, Karjakatu 35 B, FI-20520, Turku, Finland.
4
DarwinHealth Inc., 3960 Broadway, Suite 540, New York, NY, 10032, USA.
5
Lester and Sue Smith Breast Center, Baylor College of Medicine, One Baylor Plaza - BCM600, Houston, TX, 77030, USA.
6
Center for Spatial Systems Biomedicine, Oregon Health & Science University, 2730 SW Moody Avenue, Portland, OR, 97201, USA.
7
Department of Industrial Engineering and Operations Research, University of California at Berkeley, 4141 Etcheverry Hall, Berkeley, CA, 94720, USA.
8
Department of Systems Biology, Irving Cancer Research Center, Columbia University, 1130 St. Nicholas Avenue, 8th Floor, New York, NY, 10032, USA.
9
Department of Biochemistry and Molecular Biology, Baylor College of Medicine, One Baylor Plaza - BCM125, Houston, TX, 77030, USA.
10
Knight Cancer Institute, Oregon Health & Science University, 3181 SW Sam Jackson Park Road, Portland, OR, 97239, USA.
11
Center for Spatial Systems Biomedicine, Oregon Health & Science University, 2730 SW Moody Avenue, Portland, OR, 97201, USA. grayjo@ohsu.edu.
12
Knight Cancer Institute, Oregon Health & Science University, 3181 SW Sam Jackson Park Road, Portland, OR, 97239, USA. grayjo@ohsu.edu.
13
Department of Molecular and Medical Genetics, Oregon Health & Science University, 3181 SW Sam Jackson Park Road L103, Portland, OR, 97239, USA. searsr@ohsu.edu.
14
Center for Spatial Systems Biomedicine, Oregon Health & Science University, 2730 SW Moody Avenue, Portland, OR, 97201, USA. searsr@ohsu.edu.
15
Knight Cancer Institute, Oregon Health & Science University, 3181 SW Sam Jackson Park Road, Portland, OR, 97239, USA. searsr@ohsu.edu.

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.

PMID:
30232459
PMCID:
PMC6145927
DOI:
10.1038/s41467-018-05729-w
[Indexed for MEDLINE]
Free PMC Article

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