Mouse models for ROS1-fusion-positive lung cancers and their application to the analysis of multikinase inhibitor efficiency.
Mouse models for ROS1-fusion-positive lung cancers and their application to the analysis of multikinase inhibitor efficiency.
复制标题
ROS1 融合阳性肺癌小鼠模型及其在多激酶抑制剂效率分析中的应用。
DOI：
10.1093/carcin/bgw028
复制
发表时间：
2016
期刊：
影响因子：
4.7
通讯作者：
Noda T.
中科院分区：
文献类型：
--
作者：
Inoue M;Toki H;Matsui J;Togashi Y;Dobashi A;Fukumura R;Gondo Y;Minowa O;Tanaka N;Mori S;Takeuchi K;Noda T.
据报道，1-2% 的人类非小细胞肺癌病例中存在由染色体重排引起的 ROS1 融合基因。迄今为止，已鉴定出超过 10 个不同的 ROS1 融合基因，包括断点变异。在这项研究中，为了研究最常检测到的融合体之一 CD74-ROS1 以及在多项研究中也报道过的另一种 SDC4-ROS1 融合体的体内致癌活性，我们生成了转基因 (TG) 小鼠品系，该小鼠品系在 II 型肺泡细胞中特异性表达两种 ROS1 融合基因中的任一种。所有 TG 品系中的小鼠均在肺部出现致瘤性结节，并且两个 TG 小鼠品系中的少数品系均表现出早发性结节发展（出生后 2-4 周，肺部出现多个肿瘤病变）；因此，选择这两个菌株进行进一步研究。两个品系未经治疗的 TG 小鼠的肿瘤均逐渐发展，而接受口服 ALK/MET/ROS1 抑制剂克唑替尼和 ALK/ROS1 抑制剂 ASP3026 的小鼠的肿瘤负荷显着减少。总的来说，这些数据表明这两个 ROS1 融合基因中的每一个都充当体内肺腺癌发病机制的驱动因素。本研究中开发的 TG 小鼠有望成为探索针对 ROS1 融合阳性肺癌的新型治疗药物的宝贵工具。
ROS1-fusion genes, resulting from chromosomal rearrangement, have been reported in 1–2% of human non-small cell lung cancer cases. More than 10 distinctROS1-fusion genes, including break-point variants, have been identified to date. In this study, to investigate thein vivooncogenic activities of one of the most frequently detected fusions,CD74-ROS1, as well as anotherSDC4-ROS1fusion that has also been reported in several studies, we generated transgenic (TG) mouse strains that express either of the twoROS1-fusion genes specifically in lung alveolar type II cells. Mice in all TG lines developed tumorigenic nodules in the lung, and a few strains of both TG mouse lines demonstrated early-onset nodule development (multiple tumor lesions present in the lung at 2–4 weeks after birth); therefore, these two strains were selected for further investigation. Tumors developed progressively in the untreated TG mice of both lines, whereas those receiving oral administration of an ALK/MET/ROS1 inhibitor, crizotinib, and an ALK/ROS1 inhibitor, ASP3026, showed marked reduction in the tumor burden. Collectively, these data suggest that each of these twoROS1-fusion genes acts as a driver for the pathogenesis of lung adenocarcinomain vivo. The TG mice developed in this study are expected to serve as valuable tools for exploring novel therapeutic agents againstROS1-fusion-positive lung cancer.