背景:原癌基因ROS1编码酪氨酸激酶/胰岛素受体家族的内在I型膜蛋白。ROS1通过自身突变或重排促进各种恶性肿瘤的进展。已经进行了针对ROS1的酪氨酸激酶抑制剂的研究,有些已被FDA批准用于临床。然而,与ROS1抑制剂相关的不良反应和耐药机制尚不清楚.此外,下一代ROS1抑制剂,具有治疗中枢神经系统转移和缓解内源性耐药的优势,仍处于临床试验阶段。
方法:在本研究中,我们检索了近年来报道ROS1的作用机制和临床应用的相关文章;系统综述了ROS1的生物学机制,诊断方法,以及ROS1抑制剂的研究进展;为ROS1靶向治疗的未来提供了展望。
结果:ROS1在恶性肿瘤中表达最多。目前只有少数ROS1激酶抑制剂被批准用于NSCLC。其他TKIs治疗NSCLC和其他恶性肿瘤的疗效尚未确定.对于不良事件或对ROS1靶向治疗的耐药性,目前尚无有效的标准治疗方法。下一代TKIs似乎能够克服抵抗并延迟中枢神经系统转移,但不良反应发生率更高。
结论:关于ROS1及其融合伙伴定位的下一代TKI的进一步研究,靶向药物的结合位点,并且需要与其他药物共同给药。在临床实践中,TKIs与化疗或免疫治疗之间的相关性需要进一步研究。
BACKGROUND: 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.
METHODS: 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.
RESULTS: 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.
CONCLUSIONS: 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.