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Mol Cancer Ther. 2016 Jul;15(7):1768-77. doi: 10.1158/1535-7163.MCT-15-1008. Epub 2016 May 16.

Chromatin Regulators as a Guide for Cancer Treatment Choice.

Author information

1
Institut Curie, PSL Research University, CNRS, UMR3664, Equipe Labellisée Ligue contre le Cancer, Paris, France. Sorbonne Universités, UPMC Universite Paris 06, CNRS, UMR3664, Paris, France. zachary.gurard-levin@curie.fr genevieve.almouzni@curie.fr.
2
Institut Curie, PSL Research University, CNRS, UMR3664, Equipe Labellisée Ligue contre le Cancer, Paris, France. Sorbonne Universités, UPMC Universite Paris 06, CNRS, UMR3664, Paris, France.
3
Spanish National Cancer Research Centre (CNIO), c/Melchor Fernandez, Almagro, Madrid, Spain.
4
DITEP (Département d'Innovations Thérapeutiques et Essais Précoces), Gustave Roussy, France. Inserm Unit U981, Gustave Roussy, Villejuif, France. Université Paris Saclay, Université Paris-Sud, Faculté de Médicine, Le Kremlin Bicêtre, France.
5
Developmental Therapeutics Branch and Laboratory of Molecular Pharmacology, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland.
6
Institut Curie, PSL Research University, Translational Research Department, Genomics Platform, Paris, France.
7
Institut Curie, Medical Oncology, Paris, France.

Abstract

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.

PMID:
27196757
PMCID:
PMC4936925
DOI:
10.1158/1535-7163.MCT-15-1008
[Indexed for MEDLINE]
Free PMC Article

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