Inoue Maki, Toki Hideaki, Matsui Junko, Togashi Yuki, Dobashi Akito, Fukumura Ryutaro, Gondo Yoichi, Minowa Osamu, Tanaka Norio, Mori Seiichi, Takeuchi Kengo, Noda Tetsuo
Team for Advanced Development and Evaluation of Human Disease Models, RIKEN BioResource Center, Tsukuba 305-0074, Japan, Division of Cell Biology.
Team for Advanced Development and Evaluation of Human Disease Models, RIKEN BioResource Center, Tsukuba 305-0074, Japan.
Carcinogenesis. 2016 May;37(5):452-60. doi: 10.1093/carcin/bgw028. Epub 2016 Mar 10.
ROS1-fusion genes, resulting from chromosomal rearrangement, have been reported in 1-2% of human non-small cell lung cancer cases. More than 10 distinct ROS1-fusion genes, including break-point variants, have been identified to date. In this study, to investigate the in vivo oncogenic activities of one of the most frequently detected fusions, CD74-ROS1, as well as another SDC4-ROS1 fusion that has also been reported in several studies, we generated transgenic (TG) mouse strains that express either of the two ROS1-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 two ROS1-fusion genes acts as a driver for the pathogenesis of lung adenocarcinoma in vivo The TG mice developed in this study are expected to serve as valuable tools for exploring novel therapeutic agents against ROS1-fusion-positive lung cancer.
染色体重排产生的ROS1融合基因在1%-2%的人类非小细胞肺癌病例中被报道。迄今为止，已鉴定出10多种不同的ROS1融合基因，包括断点变体。在本研究中，为了研究最常检测到的融合基因之一CD74-ROS1以及另一项多项研究中也有报道的SDC4-ROS1融合基因在体内的致癌活性，我们构建了在肺泡II型细胞中特异性表达这两种ROS1融合基因之一的转基因（TG）小鼠品系。所有TG系的小鼠肺部均出现致瘤性结节，且两个TG小鼠品系的一些毒株表现出早期结节发育（出生后2-4周肺部出现多个肿瘤病变）；因此，选择这两个品系进行进一步研究。两个品系未经治疗的TG小鼠肿瘤均逐渐发展，而口服ALK/MET/ROS1抑制剂克唑替尼和ALK/ROS1抑制剂ASP3026的小鼠肿瘤负担明显减轻。总体而言，这些数据表明这两种ROS1融合基因中的每一种都在体内作为肺腺癌发病机制的驱动因素。本研究中构建的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有价值工具。
