ROS-1 NSCLC therapy resistance mechanism

: ROS1 -rearrangements occur in 1–2% of advanced non-small cell lung cancer (NSCLC) and define a distinct molecular subgroup. In the last decade, the development of molecularly targeted therapy has changed the standard of care for NSCLC patients harboring ROS1 and other driver mutations. The multitargeted MET/ALK/ROS1 tyrosine kinase inhibitor (TKI) crizotinib significantly improves overall survival for these patients; however, resistance to crizotinib invariably occurs, leading to disease progression. Several resistance mechanisms to crizotinib have been reported, including pharmacokinetic/dynamic failure, biological acquired resistance by secondary point mutations in the ROS1 kinase domain, bypass tracks, and phenotypic changes. Next-generation TKIs can be clinically active against ROS1 -rearranged NSCLC after progression to crizotinib, depending on the acquired resistance mechanism, or have substantial intracranial activity compared to crizotinib. Understanding the mechanisms of resistance to ROS1 TKI is critical to develop selective therapies. Thus, contemporary approaches are essential to improve outcomes with subsequent treatments in patients with ROS1 -rearranged lung cancer. Tissue or blood-based next generation sequencing (NGS) can help to identify the resistance mechanism to ROS1 TKI and may be considered after tumor progression in order to better select further lines of targeted therapy, although prospective validation of this therapeutic approach is needed. In this review, we perform a comprehensive analysis of ROS1 fusions in NSCLC, resistance mechanism to ROS1 targeted therapies, and future strategies. have been tested in the first-line. Resistance mechanism to different TKIs used in the front-line treatment other than crizotinib for ROS1 -positive cancer patients can modified subsequent therapies.