ROS1, a proto-oncogene, encodes a receptor tyrosine kinase [1,2,3]. Its physiological role in humans remains unknown, but it is homologous to the v-Ros sequence of University of Manchester tumours virus 2 (UR2) sarcoma virus, and its ligands are still under investigation [2]. When somatic chromosomal fusions involving ROS1 occur, chimeric oncoproteins are produced, driving various cancers in both adult and paediatric patients [1]. These oncoproteins promote cell proliferation, activation, and cell cycle progression by activating downstream signalling pathways, accelerating cancer development, especially in non-small-cell lung cancer (NSCLC) [2].

ROS1-directed tyrosine kinase inhibitors (TKIs) are effective against ROS1-fusion-positive cancers [1]. However, resistance to these TKIs can emerge in patients. Factors influencing resistance include the subcellular localization of the ROS1 oncoprotein and TKI properties [1]. Higher-affinity next-generation ROS1 TKIs have been developed to improve intracranial activity and mitigate resistance mechanisms, demonstrating clinical efficacy [1]. In NSCLC, ROS1 gene fusions are an oncogenic driver, accounting for 1%-2% of cases, and patients are initially treated with TKIs, but tumors eventually develop resistance through secondary kinase mutations or bypass signalling pathways [4,5].

In conclusion, ROS1, through its role in encoding a receptor tyrosine kinase and formation of chimeric oncoproteins upon chromosomal fusion, is significantly involved in cancer development, especially NSCLC. The study of ROS1-dependent cancers and the development of ROS1-targeted therapies, including understanding resistance mechanisms, contribute to the advancement of cancer treatment strategies for ROS1-related malignancies [1-6].