Ercc1 Deficiency Promotes Tumorigenesis and Increases Cisplatin Sensitivity in a Tp53 Context-Specific Manner
Ercc1 Deficiency Promotes Tumorigenesis and Increases Cisplatin Sensitivity in a Tp53 Context-Specific Manner
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DOI：
10.1158/1541-7786.mcr-16-0094
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发表时间：
2016-11-01
影响因子：
5.2
通讯作者：
Reinhardt, Hans Christian
中科院分区：
文献类型：
--
作者：
Jokic, Mladen;Vlasic, Ignacija;Reinhardt, Hans Christian
KRAS 突变肺腺癌是最常见的癌症实体之一，在晚期阶段，通常由于对化疗的获得性耐药而表现出不良预后，而化疗仍然主要基于含顺铂的联合方案。顺铂耐药机制已被广泛研究，ERCC1 由于其在顺铂诱导的 DNA 损伤修复中的核心作用而成为关键参与者。然而，临床数据尚未明确证实 ERCC1 状态可以作为顺铂治疗反应的预测因子。因此，我们采用类似于人肺腺癌的 Kras 驱动肺腺癌的本地小鼠模型来研究 Ercc1 在顺铂治疗反应中的作用。我们的数据表明，Tp53 缺陷型小鼠肺腺癌中的 Ercc1 缺陷会诱导更具侵袭性的肿瘤表型，从而对顺铂治疗表现出更高的敏感性。此外，在我们的模型中，顺铂治疗后复发的肿瘤会产生强大的依托泊苷敏感性，该敏感性与 Ercc1 状态无关，并且仅取决于之前的顺铂暴露。我们的结果为进一步研究根据功能性 ERCC1 和突变 TP53 状态预选肺腺癌患者的可能性提供了坚实的基础，其中功能性 ERCC1 不健全的患者可能受益于序贯顺铂和依托泊苷化疗。 (C)2016 AACR。
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.