Heßmann, Elisabeth

[["dc.bibliographiccitation.firstpage","6163"],["dc.bibliographiccitation.issue","24"],["dc.bibliographiccitation.journal","Cancers"],["dc.bibliographiccitation.volume","13"],["dc.contributor.affiliation","Ewers, Katharina M.; 1Institute of Molecular Oncology, Göttingen Center of Molecular Biosciences (GZMB), University Medical Center Göttingen, Justus von Liebig Weg 11, 37077 Göttingen, Germany; katharina.ewers@med.uni-goettingen.de (K.M.E.); tabea.quilitz@stud.uni-goettingen.de (T.Q.); anna.magerhans@med.uni-goettingen.de (A.M.)"],["dc.contributor.affiliation","Patil, Shilpa; 2Clinical Research Unit 5002, KFO5002, University Medical Center Göttingen, 37075 Göttingen, Germany; shilpapatil528@gmail.com (S.P.); wkopp@med.uni-goettingen.de (W.K.); elisabeth.hessmann@med.uni-goettingen.de (E.H.)"],["dc.contributor.affiliation","Kopp, Waltraut; 2Clinical Research Unit 5002, KFO5002, University Medical Center Göttingen, 37075 Göttingen, Germany; shilpapatil528@gmail.com (S.P.); wkopp@med.uni-goettingen.de (W.K.); elisabeth.hessmann@med.uni-goettingen.de (E.H.)"],["dc.contributor.affiliation","Thomale, Jürgen; 4Institute of Cell Biology (Cancer Research), University of Duisburg-Essen Medical School, 45141 Essen, Germany; juergen.thomale@uni-due.de"],["dc.contributor.affiliation","Quilitz, Tabea; 1Institute of Molecular Oncology, Göttingen Center of Molecular Biosciences (GZMB), University Medical Center Göttingen, Justus von Liebig Weg 11, 37077 Göttingen, Germany; katharina.ewers@med.uni-goettingen.de (K.M.E.); tabea.quilitz@stud.uni-goettingen.de (T.Q.); anna.magerhans@med.uni-goettingen.de (A.M.)"],["dc.contributor.affiliation","Magerhans, Anna; 1Institute of Molecular Oncology, Göttingen Center of Molecular Biosciences (GZMB), University Medical Center Göttingen, Justus von Liebig Weg 11, 37077 Göttingen, Germany; katharina.ewers@med.uni-goettingen.de (K.M.E.); tabea.quilitz@stud.uni-goettingen.de (T.Q.); anna.magerhans@med.uni-goettingen.de (A.M.)"],["dc.contributor.affiliation","Wang, Xin; 5Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences, Guangzhou 510080, China; xin.wang@uni-goettingen.de"],["dc.contributor.affiliation","Hessmann, Elisabeth; 2Clinical Research Unit 5002, KFO5002, University Medical Center Göttingen, 37075 Göttingen, Germany; shilpapatil528@gmail.com (S.P.); wkopp@med.uni-goettingen.de (W.K.); elisabeth.hessmann@med.uni-goettingen.de (E.H.)"],["dc.contributor.affiliation","Dobbelstein, Matthias; 1Institute of Molecular Oncology, Göttingen Center of Molecular Biosciences (GZMB), University Medical Center Göttingen, Justus von Liebig Weg 11, 37077 Göttingen, Germany; katharina.ewers@med.uni-goettingen.de (K.M.E.); tabea.quilitz@stud.uni-goettingen.de (T.Q.); anna.magerhans@med.uni-goettingen.de (A.M.)"],["dc.contributor.author","Ewers, Katharina M."],["dc.contributor.author","Patil, Shilpa"],["dc.contributor.author","Kopp, Waltraut"],["dc.contributor.author","Thomale, Jürgen"],["dc.contributor.author","Quilitz, Tabea"],["dc.contributor.author","Magerhans, Anna"],["dc.contributor.author","Wang, Xin"],["dc.contributor.author","Hessmann, Elisabeth"],["dc.contributor.author","Dobbelstein, Matthias"],["dc.contributor.editor","Wong, David"],["dc.date.accessioned","2022-02-01T10:31:44Z"],["dc.date.available","2022-02-01T10:31:44Z"],["dc.date.issued","2021"],["dc.date.updated","2022-02-09T13:20:08Z"],["dc.description.abstract","To improve the treatment of pancreatic ductal adenocarcinoma (PDAC), a promising strategy consists of personalized chemotherapy based on gene expression profiles. Investigating a panel of PDAC-derived human cell lines, we found that their sensitivities towards cisplatin fall in two distinct classes. The platinum-sensitive class is characterized by the expression of GATA6, miRNA-200a, and miRNA-200b, which might be developable as predictive biomarkers. In the case of resistant PDAC cells, we identified a synergism of cisplatin with HSP90 inhibitors. Mechanistic explanations of this synergy include the degradation of Fanconi anemia pathway factors upon HSP90 inhibition. Treatment with the drug combination resulted in increased DNA damage and chromosome fragmentation, as we have reported previously for ovarian cancer cells. On top of this, HSP90 inhibition also enhanced the accumulation of DNA-bound platinum. We next investigated an orthotopic syngeneic animal model consisting of tumors arising from KPC cells (LSL-KrasG12D/+; LSL-Trp53R172H/+; Pdx-1-Cre, C57/BL6 genetic background). Here again, when treating established tumors, the combination of cisplatin with the HSP90 inhibitor onalespib was highly effective and almost completely prevented further tumor growth. We propose that the combination of platinum drugs and HSP90 inhibitors might be worth testing in the clinics for the treatment of cisplatin-resistant PDACs."],["dc.description.abstract","To improve the treatment of pancreatic ductal adenocarcinoma (PDAC), a promising strategy consists of personalized chemotherapy based on gene expression profiles. Investigating a panel of PDAC-derived human cell lines, we found that their sensitivities towards cisplatin fall in two distinct classes. The platinum-sensitive class is characterized by the expression of GATA6, miRNA-200a, and miRNA-200b, which might be developable as predictive biomarkers. In the case of resistant PDAC cells, we identified a synergism of cisplatin with HSP90 inhibitors. Mechanistic explanations of this synergy include the degradation of Fanconi anemia pathway factors upon HSP90 inhibition. Treatment with the drug combination resulted in increased DNA damage and chromosome fragmentation, as we have reported previously for ovarian cancer cells. On top of this, HSP90 inhibition also enhanced the accumulation of DNA-bound platinum. We next investigated an orthotopic syngeneic animal model consisting of tumors arising from KPC cells (LSL-KrasG12D/+; LSL-Trp53R172H/+; Pdx-1-Cre, C57/BL6 genetic background). Here again, when treating established tumors, the combination of cisplatin with the HSP90 inhibitor onalespib was highly effective and almost completely prevented further tumor growth. We propose that the combination of platinum drugs and HSP90 inhibitors might be worth testing in the clinics for the treatment of cisplatin-resistant PDACs."],["dc.identifier.doi","10.3390/cancers13246163"],["dc.identifier.eissn","2072-6694"],["dc.identifier.pii","cancers13246163"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/98936"],["dc.language.iso","en"],["dc.notes.intern","DOI-Import GROB-517"],["dc.publisher","MDPI"],["dc.relation.eissn","2072-6694"],["dc.rights","Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/)."],["dc.title","HSP90 Inhibition Synergizes with Cisplatin to Eliminate Basal-like Pancreatic Ductal Adenocarcinoma Cells"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dspace.entity.type","Publication"]]