Abstract A47: Chromatin remodeling factor SMARCA4 as a predictive biomarker of cisplatin therapy in non-small cell lung cancer
Authors: Chakraborty Arup R. , Bell Erica , Xiaokui Mo , Liu Ziyan , Shilo Konstantin , Kirste Simon , Stegmaier Petra , McNulty Maureen , Karachaliou Niki , Rosell Rafael , Bepler Gerold , Carbone David P. , Chakravarti Arnab 
Published: May 2016

Abstract
Adjuvant cisplatin-based chemotherapy is recommended for patients with completely resected non-small cell lung cancer (NSCLC). However, due to limited efficacy of this therapy, studies are required to identify biomarkers to select patients who would derive the most benefit of the therapy. SMARCA4 (also known as BRG1) and SMARCA2 (also known as BRM) are two important mutually exclusive catalytic subunits with ATPase activity of the mammalian chromatin remodeling complex SWItch/Sucrose NonFermentable (SWI/SNF). These subunits are required for mammalian development and are altered in a variety of malignancies including lung, prostate, pancreatic, breast, and colon. Several studies have reported that both SMARCA4 and SMARCA2 are required for the full activation of DNA damage response by ATM-mediated activation of γ-H2AX. As SMARCA4 is frequently deleted in many primary tumors including NSCLC, we hypothesized that the loss of SMARCA4 may enhance the sensitivity of tumor cells to chemotherapeutic agents causing DNA damage and may serve as predictive biomarkers of sensitivity for these agents. To that end, in the present study we evaluated the association between SMARCA4 and/or SMARCA2 alterations and the outcome of DNA-damaging chemotherapeutic cisplatin in NSCLC. We used a gene expression profiling microarray (n=133) from both control and treatment arms of the North American Intergroup phase III trial of adjuvant cisplatin plus vinorelbine (JBR.10). Kaplan-Meier method and log-rank tests were used to estimate and test the differences of probabilities in overall survival and disease-specific survival between expression groups and treatment arms. Multivariate Cox regression models were used while adjusting for other baseline clinical covariates. Improved five-year disease-specific survival was detected only in patients with low SMARCA4 expression when treated with adjuvant cisplatin/vinorelbine compared with the observational arm (HR=0.1, 95% CI: 0.0.0·5, P=0.001 (low); HR 1.1, 95% CI: 0·5-2.4, P=0·76 [high]). The interaction test was statistically significant (P=0.007). In contrast, no significant survival benefits were noted in patients with high SMARCA4 or high SMARCA2 expression. Taken together, these results suggest that decreased expression of chromatin remodeling factors SMARCA4 may serve as putative predictive biomarkers of platinum-based therapy (cisplatin) in NSCLC and requires further validation.
Citation Format: Arup R. Chakraborty, Erica Bell, Mo Xiaokui, Ziyan Liu, Konstantin Shilo, Simon Kirste, Petra Stegmaier, Maureen McNulty, Niki Karachaliou, Rafael Rosell, Gerold Bepler, David P. Carbone, Arnab Chakravarti. Chromatin remodeling factor SMARCA4 as a predictive biomarker of cisplatin therapy in non-small cell lung cancer. [abstract]. In: Proceedings of the AACR Special Conference on Chromatin and Epigenetics in Cancer; Sep 24-27, 2015; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2016;76(2 Suppl):Abstract nr A47.