Abstract PR02: Targeting altered SWI/SNF function through synthetic lethal RNAi screening

Abstract

Abstract The SWI/SNF family of chromatin remodeling complexes is critical for the mobilization of nucleosomes during transcription, DNA replication and repair, and cell division. SWI/SNF consists of a central ATPase subunit (BRG1 or BRM) and 10-12 additional subunits whose identity lends specificity to the complex. Abundant genomic data indicates that SWI/SNF components are frequent targets of homozygous loss of function mutations in a variety of tumor types. These loss of function mutations alter the composition and activity of the SWI/SNF complex, resulting in a tumor-specific chromatin state. In this work we describe a strategy for targeting this tumor-specific chromatin state using synthetic lethal RNAi screening. We have assembled and validated a focused shRNA library targeting 120 factors that act on chromatin, including histone methyltransferases, histone demethylases, and bromodomain-containing proteins. The Constellation shRNA library was transduced into several cell lines containing mutations in SWI/SNF components in addition to a panel of reference cell lines in order to identify factors that are specifically essential in those cell lines with altered SWI/SNF activity. Primary screening generated a list of genes that are potentially synthetically lethal with loss of function mutations in SWI/SNF components. Experiments are underway to confirm these genetic relationships and to obtain mechanistic insight into the role of these relationships in the context of chromatin biology. Most importantly, we will evaluate these genes as novel therapeutic targets in cancers with altered SWI/SNF function. This abstract is also presented as Poster A19. Citation Format: Andrew R. Conery, Adrianne Neiss, Charlie Hatton, Barbara M. Bryant, Robert J. Sims, III. Targeting altered SWI/SNF function through synthetic lethal RNAi screening. [abstract]. In: Proceedings of the AACR Precision Medicine Series: Synthetic Lethal Approaches to Cancer Vulnerabilities; May 17-20, 2013; Bellevue, WA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(5 Suppl):Abstract nr PR02.