ROS1positive

ROS1-positive refers to tumors in which the ROS1 gene is rearranged to form an oncogenic fusion protein with constitutive tyrosine kinase activity. In practice, ROS1 rearrangements most often occur in non-small cell lung cancer (NSCLC), particularly adenocarcinomas in never-smokers, but have also been reported in cholangiocarcinoma, glioblastoma and other solid tumors. The rearrangements join the 3' ROS1 kinase domain to an upstream 5' partner gene, creating a constitutively active receptor tyrosine kinase that drives tumor growth.

Diagnosis and testing are essential to identify ROS1 rearrangements and guide therapy. Fluorescence in situ hybridization (FISH) is a common method; immunohistochemistry (IHC) can screen tumors for ROS1 protein expression; next-generation sequencing (NGS) can confirm fusions and determine partner genes. Testing is often performed on tumor tissue, and liquid biopsy can detect rearrangements in some cases.

Clinical relevance and treatment for ROS1-positive cancers, particularly NSCLC, has been shaped by targeted inhibitors. Crizotinib was the first approved ROS1-targeted therapy and showed high response rates and meaningful progression-free survival, including activity in brain metastases. Entrectinib is another approved inhibitor with CNS activity and is used for ROS1-rearranged NSCLC and other ROS1 fusion tumors. After resistance to first-line inhibitors, second-generation inhibitors and clinical trials explore options such as lorlatinib and other agents. Therapeutic strategy is typically targeted therapy rather than standard chemotherapy when feasible.

Prognosis and resistance: Outcomes with ROS1 inhibitors are favorable compared with conventional chemotherapy, but resistance eventually develops in many patients, commonly via secondary mutations in the ROS1 kinase domain (e.g., G2032R). Ongoing research seeks to overcome resistance and expand indications.