Abstract 562: Alterations in chromatin remodeling pathways as a predictive biomarker of cisplatin therapy in non-small cell lung cancer

Abstract

Abstract BRG1 (SMARCA4) and BRM (SMARCA2) are two important catalytic (ATPase) components of the mammalian chromatin remodeling complex SWI/SNF. Alterations of these components have been implicated in many cancers including lung, prostate, pancreatic, breast, and colon. Several studies have reported that both BRG1 and BRM actively participate in DNA damage repair by inducing phosphorylation of γ-H2AX, stimulating nucleotide excision repair, and also regulating interstand cross-link repair. BRG1 is frequently deleted in many primary tumors and lung cancer cell lines. Therefore, we hypothesized that reduced DNA repair capacity due to loss of BRG1 may enhance the sensitivity to DNA-damaging agents and may serve as predictive biomarkers of sensitivity for these agents. The purpose of this study was to evaluate the association between BRG1 and/or BRM alterations and the outcome of platinum-based chemoradiation in resected non-small cell lung cancer (NSCLC). Using the gene profiling of the patient tumor samples from the North American Intergroup phase III trial of adjuvant cisplatin plus vinorelbine (JBR.10), we found that patients with low BRG1 (SMARCA4) or low BRM (SMARCA2) had significantly longer overall survival (OS) if they had adjuvant chemotherapy (both p<0.05, vs no-adjuvant treatment patients). Interestingly, no significant differences in the OS were observed with high SMARCA4 or high SMARCA2 expression. Collectively, this study suggests that reduced expression of SMARCA4 and SMARCA2 may serve as putative predictive biomarkers of cisplatin therapy and warrants further investigation. This study was supported by funds from the Lung Cancer Research Foundation (to EB), the Paul P. Carbone Memorial Foundation (to EB), The Ohio State University Comprehensive Cancer Center (to AC); NIH/NCI 1U10CA180850-01(to AC); NIH/NCI 1RC2CA148190 (to AC); NIH/NCI 2K12CA133250-06 (to AC); NIH/NCI/CTEP 1R01CA169368 (to AC); NIH/NCI 1R01CA11522358 (to AC), and RTOG (to AC). Citation Format: Erica Hlavin Bell, Arup Ratan Chakraborty, Xiaokui Molly Mo, David Carbone, Arnab Chakravarti. Alterations in chromatin remodeling pathways as a predictive biomarker of cisplatin therapy in non-small cell lung cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 562. doi:10.1158/1538-7445.AM2015-562