Ercc1 deficiency promotes tumorigenesis and increases cisplatin sensitivity in a Tp53 context-specific manner

Mladen Jokic*, Ignacija Vlasic, Miriam Rinneburger, Niklas Klumper, Judith Spiro, Wenzel Vogel, Anne Offermann, Christiane Kumpers, Christian Fritz, Anna Schmitt, Arina Riabinska, Maike Wittersheim, Sebastian Michels, Luka Ozretic, Alexandra Florin, Daniela Welcker, Mehmet DenizAkyuz, Michael Nowak, Martin Erkel, Jurgen WolfReinhard Buttner, Bjorn Schumacher, Jurgen Thomale, Thorsten Persigehl, David Maintz, Sven Perner, Hans Christian Reinhardt

*Korrespondierende/r Autor/-in für diese Arbeit
15 Zitate (Scopus)

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. Implications: 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.

OriginalspracheEnglisch
ZeitschriftMolecular Cancer Research
Jahrgang14
Ausgabenummer11
Seiten (von - bis)1110-1123
Seitenumfang14
ISSN1541-7786
DOIs
PublikationsstatusVeröffentlicht - 01.11.2016

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