Chromatin Regulators as a Guide for Cancer Treatment Choice

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Bibliographische Detailangaben
Zeitschriftentitel:	Molecular Cancer Therapeutics
Personen und Körperschaften:	Gurard-Levin, Zachary A., Wilson, Laurence O.W., Pancaldi, Vera, Postel-Vinay, Sophie, Sousa, Fabricio G., Reyes, Cecile, Marangoni, Elisabetta, Gentien, David, Valencia, Alfonso, Pommier, Yves, Cottu, Paul, Almouzni, Geneviève
In:	Molecular Cancer Therapeutics, 15, 2016, 7, S. 1768-1777
Format:	E-Article
Sprache:	Englisch
veröffentlicht:	American Association for Cancer Research (AACR)
Schlagwörter:	Cancer Research Oncology

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Zusammenfassung:	<jats:title>Abstract</jats:title> <jats:p>The limited capacity to predict a patient's response to distinct chemotherapeutic agents is a major hurdle in cancer management. The efficiency of a large fraction of current cancer therapeutics (radio- and chemotherapies) is influenced by chromatin structure. Reciprocally, alterations in chromatin organization may affect resistance mechanisms. Here, we explore how the misexpression of chromatin regulators—factors involved in the establishment and maintenance of functional chromatin domains—can inform about the extent of docetaxel response. We exploit Affymetrix and NanoString gene expression data for a set of chromatin regulators generated from breast cancer patient-derived xenograft models and patient samples treated with docetaxel. Random Forest classification reveals specific panels of chromatin regulators, including key components of the SWI/SNF chromatin remodeler, which readily distinguish docetaxel high-responders and poor-responders. Further exploration of SWI/SNF components in the comprehensive NCI-60 dataset reveals that the expression inversely correlates with docetaxel sensitivity. Finally, we show that loss of the SWI/SNF subunit BRG1 (SMARCA4) in a model cell line leads to enhanced docetaxel sensitivity. Altogether, our findings point toward chromatin regulators as biomarkers for drug response as well as therapeutic targets to sensitize patients toward docetaxel and combat drug resistance. Mol Cancer Ther; 15(7); 1768–77. ©2016 AACR.</jats:p>
Umfang:	1768-1777
ISSN:	1535-7163 1538-8514
DOI:	10.1158/1535-7163.mct-15-1008