Abstract 2984: Understanding the relationship between a common mutation within the SWI/SNF chromatin remodeling complex in lung cancer and treatment response.

Abstract

Abstract SWI/SNF is a chromatin remodeling complex that plays important roles in transcriptional regulation, DNA replication, and DNA repair. BRG1, one of its catalytic ATPase subunits, is a tumor suppressor that is mutated in approximately 20-30% of non-small cell lung cancers. To determine the clinical significance of BRG1 expression, non-small cell lung cancer data from The Cancer Genome Atlas was analyzed and showed that patients with stage II, high-BRG1 tumors have a higher overall survival than patients with stage II, low-BRG1 disease probably due to differences in genomic instability. BRG1’s involvement in multiple DNA repair pathways likely results in a decreased ability of BRG1-deficient tumor cells to repair damage, which underlies our hypothesis that DNA damaging therapies may be the best treatment for patients harboring deficient BRG1. In order to study the effects of DNA damage on BRG1-positive and BRG1-negative cells, we utilized ionizing radiation, ABT-888 (a PARP inhibitor), mitomycin C, and cisplatin to test BRG1’s role in double-strand break repair, base excision repair, nucleotide excision repair, and interstrand cross-link repair. Cell lines expressing a functional BRG1 (HeLa and H520) were approximately 2-4-fold less sensitive to radiation than cells without BRG1 (C33A and A427). Likewise, HeLa cells were about 4-fold less sensitive to cisplatin, a DNA crosslinking agent, than were C33A cells. We will present data from these assays in a panel of BRG1-positive and BRG1-negative non-small cell lung cancer cell lines, and in BRG1 knockdown and knock-in models. To ascertain the effect of BRG1 loss on the expression of genes involved in related pathways, BRG1-positive and BRG1-negative HeLa cells were analyzed with RT-PCR arrays. We found statistically significant dysregulation of genes involved in several pathways, including chromatin remodeling (SMARCA2, SMARCB1, and INO80) and DNA repair (XRCC4, CDK7, GTF2H1, and GTF2H2). We are also using RT-PCR arrays to study the panel of BRG1-positive and BRG1-negative cell lines. Elucidating novel roles for BRG1 in DNA repair pathways and determining its molecular targets will help identify the best treatment strategy for patients lacking functional BRG1, and may have the potential to increase the life expectancy of lung cancer patients. Citation Format: Maureen McNulty, Simon Kirste, Jinwei Hu, Udit Singhal, Ziyan Liu, Petra Stegmaier, Daniel Dressler, Arnab Chakravarti, Erica Bell. Understanding the relationship between a common mutation within the SWI/SNF chromatin remodeling complex in lung cancer and treatment response. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2984. doi:10.1158/1538-7445.AM2013-2984