title: Ercc1 Deficiency Promotes Tumorigenesis and Increases Cisplatin Sensitivity in a Tp53 Context-Specific Manner.
abstract: KRAS-mutant lung adenocarcinoma is among the most common cancer entities and, in advanced stages, typically displays poor prognosis due to acquired resistance against chemotherapy, which is still largely based on cisplatin-containing combination regimens. Mechanisms of cisplatin resistance have been extensively investigated, and ERCC1 has emerged as a key player due to its central role in the repair of cisplatin-induced DNA lesions. However, clinical data have not unequivocally confirmed ERCC1 status as a predictor of the response to cisplatin treatment. Therefore, we employed an autochthonous mouse model of Kras-driven lung adenocarcinoma resembling human lung adenocarcinoma to investigate the role of Ercc1 in the response to cisplatin treatment. Our data show that Ercc1 deficiency in Tp53-deficient murine lung adenocarcinoma induces a more aggressive tumor phenotype that displays enhanced sensitivity to cisplatin treatment. Furthermore, tumors that relapsed after cisplatin treatment in our model develop a robust etoposide sensitivity that is independent of the Ercc1 status and depends solely on previous cisplatin exposure. Our results provide a solid rationale for further investigation of the possibility of preselection of lung adenocarcinoma patients according to the functional ERCC1- and mutational TP53 status, where functionally ERCC1-incompetent patients might benefit from sequential cisplatin and etoposide chemotherapy.
  
  
  
  This study provides a solid rationale for the stratification of lung adenocarcinoma patients according to the functional ERCC1- and mutational TP53 status, where functionally ERCC1-incompetent patients could benefit from sequential cisplatin and etoposide chemotherapy. Mol Cancer Res; 14(11); 1110-23. ©2016 AACR.
authors: Department I of Internal Medicine, University Hospital of Cologne, Weyertal 115B, 50931, Cologne, Germany. mladen.jokic@uk-koeln.de.|Cologne Excellence Cluster on Cellular Stress Response in Aging-Associated Diseases, University of Cologne, Weyertal 115B, 50931, Cologne, Germany.
authors: Mladen
authors: M
authors: Jokić
authors: Department I of Internal Medicine, University Hospital of Cologne, Weyertal 115B, 50931, Cologne, Germany.|Cologne Excellence Cluster on Cellular Stress Response in Aging-Associated Diseases, University of Cologne, Weyertal 115B, 50931, Cologne, Germany.
authors: Ignacija
authors: I
authors: Vlašić
authors: Department I of Internal Medicine, University Hospital of Cologne, Weyertal 115B, 50931, Cologne, Germany.|Cologne Excellence Cluster on Cellular Stress Response in Aging-Associated Diseases, University of Cologne, Weyertal 115B, 50931, Cologne, Germany.
authors: Miriam
authors: M
authors: Rinneburger
authors: Pathology of the University Medical Center Schleswig-Holstein, Campus Luebeck and the Research Center Borstel, Leibniz Center for Medicine and Biosciences, 23538 Luebeck and 23845 Borstel, Germany.
authors: Niklas
authors: N
authors: Klümper
authors: Department of Radiology, University Hospital of Cologne, Kerpener Str. 62, 50937, Cologne, Germany.
authors: Judith
authors: J
authors: Spiro
authors: Pathology of the University Medical Center Schleswig-Holstein, Campus Luebeck and the Research Center Borstel, Leibniz Center for Medicine and Biosciences, 23538 Luebeck and 23845 Borstel, Germany.
authors: Wenzel
authors: W
authors: Vogel
authors: Pathology of the University Medical Center Schleswig-Holstein, Campus Luebeck and the Research Center Borstel, Leibniz Center for Medicine and Biosciences, 23538 Luebeck and 23845 Borstel, Germany.
authors: Anne
authors: A
authors: Offermann
authors: Pathology of the University Medical Center Schleswig-Holstein, Campus Luebeck and the Research Center Borstel, Leibniz Center for Medicine and Biosciences, 23538 Luebeck and 23845 Borstel, Germany.
authors: Christiane
authors: C
authors: Kümpers
authors: Department I of Internal Medicine, University Hospital of Cologne, Weyertal 115B, 50931, Cologne, Germany.|Cologne Excellence Cluster on Cellular Stress Response in Aging-Associated Diseases, University of Cologne, Weyertal 115B, 50931, Cologne, Germany.
authors: Christian
authors: C
authors: Fritz
authors: Department I of Internal Medicine, University Hospital of Cologne, Weyertal 115B, 50931, Cologne, Germany.|Cologne Excellence Cluster on Cellular Stress Response in Aging-Associated Diseases, University of Cologne, Weyertal 115B, 50931, Cologne, Germany.
authors: Anna
authors: A
authors: Schmitt
authors: Department I of Internal Medicine, University Hospital of Cologne, Weyertal 115B, 50931, Cologne, Germany.|Cologne Excellence Cluster on Cellular Stress Response in Aging-Associated Diseases, University of Cologne, Weyertal 115B, 50931, Cologne, Germany.
authors: Arina
authors: A
authors: Riabinska
authors: Institute of Pathology, University Hospital of Cologne, Kerpener Str. 62, 50937, Cologne, Germany.
authors: Maike
authors: M
authors: Wittersheim
authors: Department I of Internal Medicine, University Hospital of Cologne, Kerpener Str. 62, 50937, Cologne, Germany.
authors: Sebastian
authors: S
authors: Michels
authors: Institute of Pathology, University Hospital of Cologne, Kerpener Str. 62, 50937, Cologne, Germany.
authors: Luka
authors: L
authors: Ozretić
authors: Institute of Pathology, University Hospital of Cologne, Kerpener Str. 62, 50937, Cologne, Germany.
authors: Alexandra
authors: A
authors: Florin
authors: Department I of Internal Medicine, University Hospital of Cologne, Weyertal 115B, 50931, Cologne, Germany.|Cologne Excellence Cluster on Cellular Stress Response in Aging-Associated Diseases, University of Cologne, Weyertal 115B, 50931, Cologne, Germany.|Department II of Internal Medicine, University Hospital Cologne, Kerpener Str. 62, 50937, Cologne, Germany.
authors: Daniela
authors: D
authors: Welcker
authors: Institute for genome stability in ageing and disease, CECAD Research Center, Joseph-Stelzmann-Str. 26, 50931, Cologne, Germany.
authors: Mehmet Deniz
authors: MD
authors: Akyuz
authors: Institute of Pathology, University Hospital Bonn, Sigmund-Freud-Str. 25, 53127, Bonn, Germany.
authors: Michael
authors: M
authors: Nowak
authors: Institute for Cell Biology, University Hospital Essen, Hufelandstraβe 55, 45122, Essen, Germany.
authors: Martin
authors: M
authors: Erkel
authors: Department I of Internal Medicine, University Hospital of Cologne, Kerpener Str. 62, 50937, Cologne, Germany.
authors: Jürgen
authors: J
authors: Wolf
authors: Institute of Pathology, University Hospital of Cologne, Kerpener Str. 62, 50937, Cologne, Germany.
authors: Reinhard
authors: R
authors: Büttner
authors: Institute for genome stability in ageing and disease, CECAD Research Center, Joseph-Stelzmann-Str. 26, 50931, Cologne, Germany.
authors: Björn
authors: B
authors: Schumacher
authors: Institute for Cell Biology, University Hospital Essen, Hufelandstraβe 55, 45122, Essen, Germany.
authors: Jürgen
authors: J
authors: Thomale
authors: Department of Radiology, University Hospital of Cologne, Kerpener Str. 62, 50937, Cologne, Germany.
authors: Thorsten
authors: T
authors: Persigehl
authors: Department of Radiology, University Hospital of Cologne, Kerpener Str. 62, 50937, Cologne, Germany.
authors: David
authors: D
authors: Maintz
authors: Pathology of the University Medical Center Schleswig-Holstein, Campus Luebeck and the Research Center Borstel, Leibniz Center for Medicine and Biosciences, 23538 Luebeck and 23845 Borstel, Germany.
authors: Sven
authors: S
authors: Perner
authors: Department I of Internal Medicine, University Hospital of Cologne, Weyertal 115B, 50931, Cologne, Germany.|Cologne Excellence Cluster on Cellular Stress Response in Aging-Associated Diseases, University of Cologne, Weyertal 115B, 50931, Cologne, Germany.
authors: Hans Christian
authors: HC
authors: Reinhardt
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy* / Q000235:genetics; D000077192:Adenocarcinoma of Lung; D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002945:Cisplatin / Q000008:administration & dosage* / Q000494:pharmacology; D004268:DNA-Binding Proteins / Q000172:deficiency*; D019008:Drug Resistance, Neoplasm; D004720:Endonucleases / Q000172:deficiency*; D005047:Etoposide / Q000008:administration & dosage / Q000494:pharmacology; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics; D051379:Mice; D009154:Mutation; D057285:Precision Medicine; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics*; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*
chemical_list: D004268:DNA-Binding Proteins; D016159:Tumor Suppressor Protein p53; D005047:Etoposide; D004720:Endonucleases; C499360:Ercc1 protein, mouse; C495971:Hras protein, mouse; D016283:Proto-Oncogene Proteins p21(ras); D002945:Cisplatin