Jokic, Mladen, Vlasic, Ignacija, Rinneburger, Miriam ORCID: 0000-0003-3980-931X, Kluemper, Niklas, Spiro, Judith, Vogel, Wenzel, Offermann, Anne, Kuempers, Christiane, Fritz, Christian, Schmitt, Anna, Riabinska, Arina, Wittersheim, Maike, Michels, Sebastian, Ozretic, Luka, Florin, Alexandra, Welcker, Daniela, Akyuz, Mehmet Deniz, Nowak, Michael, Erkel, Martin, Wolf, Juergen, Buettner, Reinhard, Schumacher, Bjoern, Thomale, Juergen, Persigehl, Thorsten, Maintz, David, Perner, Sven and Reinhardt, Hans Christian (2016). Ercc1 Deficiency Promotes Tumorigenesis and Increases Cisplatin Sensitivity in a Tp53 Context-Specific Manner. Mol. Cancer Res., 14 (11). S. 1110 - 1124. PHILADELPHIA: AMER ASSOC CANCER RESEARCH. ISSN 1557-3125

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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. (C)2016 AACR.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Jokic, MladenUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Vlasic, IgnacijaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Rinneburger, MiriamUNSPECIFIEDorcid.org/0000-0003-3980-931XUNSPECIFIED
Kluemper, NiklasUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Spiro, JudithUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Vogel, WenzelUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Offermann, AnneUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kuempers, ChristianeUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Fritz, ChristianUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schmitt, AnnaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Riabinska, ArinaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Wittersheim, MaikeUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Michels, SebastianUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ozretic, LukaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Florin, AlexandraUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Welcker, DanielaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Akyuz, Mehmet DenizUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Nowak, MichaelUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Erkel, MartinUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Wolf, JuergenUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Buettner, ReinhardUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schumacher, BjoernUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Thomale, JuergenUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Persigehl, ThorstenUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Maintz, DavidUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Perner, SvenUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Reinhardt, Hans ChristianUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-256829
DOI: 10.1158/1541-7786.MCR-16-0094
Journal or Publication Title: Mol. Cancer Res.
Volume: 14
Number: 11
Page Range: S. 1110 - 1124
Date: 2016
Publisher: AMER ASSOC CANCER RESEARCH
Place of Publication: PHILADELPHIA
ISSN: 1557-3125
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
CELL LUNG-CANCER; NUCLEOTIDE EXCISION-REPAIR; PLATINUM-BASED CHEMOTHERAPY; MESSENGER-RNA EXPRESSION; DNA-REPAIR; PROTEIN EXPRESSION; MONOCLONAL-ANTIBODIES; NUCLEAR ABNORMALITIES; POOR-PROGNOSIS; MUTATIONSMultiple languages
Oncology; Cell BiologyMultiple languages
Refereed: Yes
URI: http://kups.ub.uni-koeln.de/id/eprint/25682

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