ROS1是人类基因组中最大的酪氨酸激酶受体。ROS1基因的重排导致肿瘤源性ROS1激酶融合蛋白，目前是患者靶向治疗中唯一经验证的生物标志物。虽然癌症基因组中存在许多ROS1体细胞错义突变，但其对催化活性和致病潜力的影响尚不明确。我们查询了AACR Genie数据库，并发现了34个ROS1酪氨酸激酶结构域的错义突变，以进一步进行分析。我们的实验发现这些突变对ROS1激酶功能有不同影响，范围从完全丧失到显著增加的催化活性。值得注意的是，ROS1酪氨酸激酶结构域中Asp2113的天冬酰胺和甘氨酸置换变体在细胞模型系统中被发现是对TKI敏感的致病变种。体内实验证明，ROS1 D2113N诱导的肿瘤形成对crizotinib和lorlatinib敏感，这是FDA批准的ROS1-TKI。总的来说，这些发现突出了ROS1酪氨酸激酶结构域内特定点突变的致瘤潜力，以及它们作为FDA批准的ROS1-TKI的治疗靶点的潜力。© 2023 The Authors. 根据CC BY 4.0许可证发布。

ROS1 is the largest receptor tyrosine kinase in the human genome. Rearrangements of the ROS1 gene result in oncogenic ROS1 kinase fusion proteins that are currently the only validated biomarkers for targeted therapy with ROS1 TKIs in patients. While numerous somatic missense mutations in ROS1 exist in the cancer genome, their impact on catalytic activity and pathogenic potential is unknown. We interrogated the AACR Genie database and identified 34 missense mutations in the ROS1 tyrosine kinase domain for further analysis. Our experiments revealed that these mutations have varying effects on ROS1 kinase function, ranging from complete loss to significantly increased catalytic activity. Notably, Asn and Gly substitutions at Asp2113 in the ROS1 kinase domain were found to be TKI-sensitive oncogenic variants in cell-based model systems. In vivo experiments showed that ROS1 D2113N induced tumor formation that was sensitive to crizotinib and lorlatinib, FDA-approved ROS1-TKIs. Collectively, these findings highlight the tumorigenic potential of specific point mutations within the ROS1 kinase domain and their potential as therapeutic targets with FDA-approved ROS1-TKIs.© 2023 The Authors. Published under the terms of the CC BY 4.0 license.