Abstract 3809: SWI/SNF aberrations sensitize pancreatic cancer cells to DNA crosslinking agents

Abstract

Abstract While gemcitabine has been the mainstay therapy for advanced pancreatic cancer, newer combination regimens (e.g. FOLFIRINOX) have extended patient survival, though carry greater toxicity. Biomarkers are needed to better stratify patients for appropriate therapy. Previously, we reported that one-third of pancreatic cancers harbor deletions or deleterious mutations in key subunits of the SWItch/Sucrose NonFermentable (SWI/SNF) chromatin remodeling complex. The SWI/SNF complex mobilizes nucleosomes on DNA, and plays a key role in modulating DNA transcription and repair. Thus, we hypothesized that pancreatic cancers with SWI/SNF aberrations might exhibit compromised DNA repair, and show increased sensitivity to DNA damaging agents. Here, we studied pancreatic cancer cell lines with deficient (or else exogenously reconstituted) SWI/SNF subunits, as well as normal pancreatic epithelial cells (HPDE) following SWI/SNF subunit knockdown. Cells were challenged with DNA damaging agents, including those used in current combination regimens, and then cell viability assayed. We found that pancreatic cells with SWI/SNF dysfunction showed markedly increased sensitivity to DNA damaging agents, and in particular DNA crosslinking agents (cisplatin and oxaliplatin). Assaying clearance of γH2AX foci confirmed that SWI/SNF dysfunction impaired DNA damage response/repair. Finally, by analyzing pancreatic cancer patient data (TCGA), we found that pancreatic cancers with SWI/SNF deficiency (subunit mutation and/or decreased expression) showed a strong trend towards extended survival with platinum containing chemo regimens. Thus, SWI/SNF dysfunction sensitizes pancreatic cancer cells to DNA crosslinking agents, and SWI/SNF mutation status may provide a useful biomarker to predict which patients are likely to benefit from platinum-containing chemotherapy regimens. Citation Format: Zhewei Shen, Jean Davidson, Jonathan Pollack. SWI/SNF aberrations sensitize pancreatic cancer cells to DNA crosslinking agents [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3809. doi:10.1158/1538-7445.AM2017-3809