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

Tyler Risom, Ellen M. Langer, Margaret P. Chapman, Juha Rantala, Andrew J. Fields, Christopher Boniface, Mariano J. Alvarez, Nicholas D. Kendsersky, Carl R. Pelz, Katherine Johnson-Camacho, Lacey E. Dobrolecki, Koei Chin, Anil J. Aswani, Nicholas J. Wang, Andrea Califano, Michael T. Lewis, Claire J. Tomlin, Paul T. Spellman, Andrew Adey, Joe W. Gray () and Rosalie C. Sears ()
Additional contact information
Tyler Risom: Oregon Health & Science University
Ellen M. Langer: Oregon Health & Science University
Margaret P. Chapman: University of California at Berkeley
Juha Rantala: Misvik Biology
Andrew J. Fields: Oregon Health & Science University
Christopher Boniface: Oregon Health & Science University
Mariano J. Alvarez: DarwinHealth Inc.
Nicholas D. Kendsersky: Oregon Health & Science University
Carl R. Pelz: Oregon Health & Science University
Katherine Johnson-Camacho: Oregon Health & Science University
Lacey E. Dobrolecki: Baylor College of Medicine
Koei Chin: Oregon Health & Science University
Anil J. Aswani: University of California at Berkeley
Nicholas J. Wang: Oregon Health & Science University
Andrea Califano: DarwinHealth Inc.
Michael T. Lewis: Baylor College of Medicine
Claire J. Tomlin: University of California at Berkeley
Paul T. Spellman: Oregon Health & Science University
Andrew Adey: Oregon Health & Science University
Joe W. Gray: Oregon Health & Science University
Rosalie C. Sears: Oregon Health & Science University

Nature Communications, 2018, vol. 9, issue 1, 1-17

Abstract: 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.

Date: 2018
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DOI: 10.1038/s41467-018-05729-w

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