Abstract LB-129: Epigenetic regulators to predict docetaxel sensitivity; a guide for treatment choice

The limited capacity to predict the response of a given patient to cancer therapy is a major hurdle in cancer management. To date, many standard-of-care chemotherapy agents act by directly binding or modifying DNA or indirectly during processes that rely on chromatin architecture, as exemplified with docetaxel. Therefore, alterations in chromatin organization may impact resistance mechanisms for these drugs. Here, we explore the mis-regulation of chromatin regulators—factors involved in the establishment and maintenance of functional chromatin domains—as a tool to predict the response to docetaxel. For a series of chromatin regulators, we exploit Affymetrix microarray and NanoString gene expression data generated from breast cancer patient derived xenograft (PDX) models, colorectal cancer organoids, and breast cancer patient samples treated with docetaxel. Random Forest classification reveals a limited set of chromatin regulators that readily distinguish docetaxel responders from non-responders. Since the candidate predictive factors feature key subunits of the chromatin remodeler SWI/SNF complex, we then explore the behavior of SWI/SNF subunits in the response to docetaxel in the large NCI-60 dataset and in cultured cells. All together, our results showcase the predictive value of chromatin regulators and reveal that the SWI/SNF chromatin remodeler associates tightly with docetaxel response in several settings. Our findings open avenues for applications as biomarkers, but also as therapeutic targets to sensitize patients towards docetaxel. These approaches offer a means to potentially combat drug resistance. Citation Format: Zachary A. Gurard-Levin, Laurence OW Wilson, Vera Pancaldi, Sophie Postel-Vinay, Fabricio G. Sousa, Cecile Reyes, Elisabetta Marangoni, David Gentien, Alfonso Valencia, Yves Pommier, Paul Cottu, Genevieve Almouzni. Epigenetic regulators to predict docetaxel sensitivity; a guide for treatment choice. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr LB-129.