Department of Orthopedics, Shengjing Hospital of China Medical University, Shenyang, Liaoning Province, China.
Medical Research Center, Shengjing Hospital of China Medical University, Shenyang, Liaoning Province, China.
Cancer Med. 2024 Apr;13(8):e7201. doi: 10.1002/cam4.7201.
The proto-oncogene ROS1 encodes an intrinsic type I membrane protein of the tyrosine kinase/insulin receptor family. ROS1 facilitates the progression of various malignancies via self-mutations or rearrangements. Studies on ROS1-directed tyrosine kinase inhibitors have been conducted, and some have been approved by the FDA for clinical use. However, the adverse effects and mechanisms of resistance associated with ROS1 inhibitors remain unknown. In addition, next-generation ROS1 inhibitors, which have the advantage of treating central nervous system metastases and alleviating endogenous drug resistance, are still in the clinical trial stage.
In this study, we searched relevant articles reporting the mechanism and clinical application of ROS1 in recent years; systematically reviewed the biological mechanisms, diagnostic methods, and research progress on ROS1 inhibitors; and provided perspectives for the future of ROS1-targeted therapy.
ROS1 is most expressed in malignant tumours. Only a few ROS1 kinase inhibitors are currently approved for use in NSCLC, the efficacy of other TKIs for NSCLC and other malignancies has not been ascertained. There is no effective standard treatment for adverse events or resistance to ROS1-targeted therapy. Next-generation TKIs appear capable of overcoming resistance and delaying central nervous system metastasis, but with a greater incidence of adverse effects.
Further research on next-generation TKIs regarding the localization of ROS1 and its fusion partners, binding sites for targeted drugs, and coadministration with other drugs is required. The correlation between TKIs and chemotherapy or immunotherapy in clinical practice requires further study.
原癌基因 ROS1 编码一种内在的 I 型跨膜蛋白酪氨酸激酶/胰岛素受体家族。ROS1 通过自身突变或重排促进多种恶性肿瘤的进展。已经对 ROS1 定向酪氨酸激酶抑制剂进行了研究，其中一些已被 FDA 批准用于临床使用。然而，ROS1 抑制剂相关的不良反应和耐药机制仍不清楚。此外，具有治疗中枢神经系统转移和缓解内源性耐药优势的下一代 ROS1 抑制剂仍处于临床试验阶段。
本研究检索了近年来报道 ROS1 在生物学机制、诊断方法和研究进展方面的相关文献；系统综述了 ROS1 抑制剂的生物机制、诊断方法和研究进展，并为 ROS1 靶向治疗的未来提供了新的视角。
ROS1 在恶性肿瘤中表达最为广泛。目前只有少数几种 ROS1 激酶抑制剂被批准用于 NSCLC，其他 TKI 对 NSCLC 和其他恶性肿瘤的疗效尚未确定。对于 ROS1 靶向治疗的不良反应或耐药性，目前尚无有效的标准治疗方法。下一代 TKI 似乎能够克服耐药性并延缓中枢神经系统转移，但不良反应发生率更高。
需要进一步研究下一代 TKI 关于 ROS1 及其融合伙伴的定位、靶向药物的结合位点以及与其他药物的联合应用。TKIs 与化疗或免疫治疗在临床实践中的相关性需要进一步研究。
