Oncotarget

Research Papers:

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

Jean Davidson, Zhewei Shen, Xue Gong and Jonathan R. Pollack _

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Oncotarget. 2018; 9:9608-9617. https://doi.org/10.18632/oncotarget.20033

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Abstract

Jean Davidson1,3,*, Zhewei Shen1,*, Xue Gong1,2 and Jonathan R. Pollack1

1Department of Pathology, Stanford University School of Medicine, Stanford, California, USA

2Department of Urology, Stanford University School of Medicine, Stanford, California, USA

3Current address: Department of Cardiovascular Research, Stanford University School of Medicine, Stanford, California, USA

*These authors contributed equally to this work

Correspondence to:

Jonathan R. Pollack, email: [email protected]

Keywords: SWI/SNF, pancreatic cancer, DNA crosslinking agents, predictive biomarkers, personalized medicine

Received: June 14, 2017     Accepted: July 26, 2017     Published: August 08, 2017

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 human pancreatic cancer cell lines with deficient (or else exogenously reconstituted) SWI/SNF subunits, as well as normal pancreatic epithelial cells 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 confirmed that SWI/SNF dysfunction impaired DNA damage response/repair. Finally, by analyzing pancreatic cancer patient data from The Cancer Genome Atlas, we found that pancreatic cancers with SWI/SNF deficiency (subunit mutation and/or decreased expression) were associated with extended patient survival specifically when treated with platinum containing 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.


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