Yu Zhi-Qiong, Wang Meng, Zhou Wen, Mao Meng-Xia, Chen Yuan-Yuan, Li Na, Peng Xiao-Chun, Cai Jun, Cai Zhi-Qiang
Department of Oncology, First Affiliated Hospital of Yangtze University, Jingzhou, PR China.
Laboratory of Oncology, Center for Molecular Medicine, Jingzhou, PR China.
J Drug Target. 2022 Sep;30(8):845-857. doi: 10.1080/1061186X.2022.2085730. Epub 2022 Jun 14.
ROS1 is a proto-oncogene encoding a receptor tyrosine protein kinase (RTK), homologous to the v - Ros sequence of University of Manchester tumours virus 2 (UR2) sarcoma virus, whose ligands are still being investigated. ROS1 fusion genes have been identified in various types of tumours. As an oncoprotein, it promotes cell proliferation, activation and cell cycle progression by activating downstream signalling pathways, accelerating the development and progression of non-small cell lung cancer (NSCLC). Studies have demonstrated that ROS1 inhibitors are effective in patients with ROS1-positive NSCLC and are used for first-line clinical treatment. These small molecule inhibitors provide a rational therapeutic option for the treatment of ROS1-positive patients. Inevitably, ROS1 inhibitor resistance mutations occur, leading to tumours recurrence or progression. Here, we comprehensively review the identified biological properties and Differential subcellular localisation of ROS1 fusion oncoprotein promotes tumours progression. We summarise recently completed and ongoing clinical trials of the classic and new ROS1 inhibitors. More importantly, we classify the complex evolving tumours cell resistance mechanisms. This review contributes to our understanding of the biological properties of ROS1 and current therapeutic advances and resistant tumours cells, and the future directions to develop ROS1 inhibitors with durable effects.
ROS1是一种原癌基因，编码一种受体酪氨酸蛋白激酶（RTK），与曼彻斯特大学肿瘤病毒2（UR2）肉瘤病毒的v-Ros序列同源，其配体仍在研究中。ROS1融合基因已在多种类型的肿瘤中被鉴定出来。作为一种癌蛋白，它通过激活下游信号通路促进细胞增殖、活化和细胞周期进程，加速非小细胞肺癌（NSCLC）的发生和发展。研究表明，ROS1抑制剂对ROS1阳性的NSCLC患者有效，并用于一线临床治疗。这些小分子抑制剂为治疗ROS1阳性患者提供了合理的治疗选择。不可避免地，会出现ROS1抑制剂耐药突变，导致肿瘤复发或进展。在此，我们全面综述了已确定的ROS1融合癌蛋白的生物学特性和不同亚细胞定位促进肿瘤进展的情况。我们总结了经典和新型ROS1抑制剂最近完成和正在进行的临床试验。更重要的是，我们对复杂且不断演变的肿瘤细胞耐药机制进行了分类。这篇综述有助于我们理解ROS1的生物学特性、当前的治疗进展和耐药肿瘤细胞，以及开发具有持久疗效的ROS1抑制剂的未来方向。
