ROS1 is a receptor tyrosine kinase that mediates cellular differentiation and proliferation through multiple signaling pathways 1. In normal physiology, ROS1 has an unknown physiological role in humans, though it plays a documented role in epithelial cell differentiation and regionalization of the proximal epididymal epithelium. ROS1 activates downstream signaling cascades including PI3 kinase-mTOR, MAPK/ERK, and STAT3 pathways through phosphorylation of substrates such as PTPN11, VAV3, and AKT1. Clinically, ROS1 fusion proteins drive oncogenic transformation in approximately 1-2% of non-small cell lung carcinoma and other malignancies including cholangiocarcinoma, gastric carcinoma, and inflammatory myofibroblastic tumors 23. These fusions produce chimeric oncoproteins with constitutive kinase activity that regulate cellular proliferation and are implicated in carcinogenesis 2. Multiple FDA-approved tyrosine kinase inhibitors—including crizotinib, entrectinib, repotrectinib, and the recently approved taletrectinib—target ROS1 fusion-positive cancers and have transformed clinical outcomes 45. However, acquired resistance invariably develops, often through solvent-front kinase domain mutations (e.g., ROS1 G2032R), necessitating sequential next-generation TKI therapy with improved CNS penetration and resistance mutation coverage 67.