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Differentiation-state Plasticity Is A Targetable Resistance Mechanism In Basal-like Breast Cancer

Tyler Risom, Ellen M Langer, M. Chapman, J. Rantala, Andrew J. Fields, Christopher T. Boniface, M. Alvarez, N. D. Kendsersky, C. Pelz, Katherine Johnson-Camacho, L. Dobrolecki, K. Chin, Anil J Aswani, N. Wang, A. Califano, M. Lewis, C. Tomlin, P. Spellman, Andrew C. Adey, J. Gray, R. Sears
Published 2018 · Biology, Medicine

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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.Resistance to therapy can be driven by intratumoral heterogeneity. Here, the authors show that drug tolerant persistent cell populations emerge during treatment, and these emergent populations arise through epigenetically mediated cell state transitions rather than sub population selection.
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