Division of Pediatric Hematology/Oncology, Department of Pediatrics, Papé Family Pediatric Research Institute, Oregon Health and Sciences University, OR, Portland, USA.
Department of Chemical Physiology, Oregon Health and Sciences University, OR, Portland, USA.
EMBO Mol Med. 2023 Oct 11;15(10):e17367. doi: 10.15252/emmm.202217367. Epub 2023 Aug 17.
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.
ROS1 是人类基因组中最大的受体酪氨酸激酶。ROS1 基因的重排导致致癌的 ROS1 激酶融合蛋白，目前是 ROS1 TKI 靶向治疗患者的唯一有效生物标志物。虽然癌症基因组中存在大量 ROS1 的体细胞错义突变，但它们对催化活性和发病潜能的影响尚不清楚。我们查询了 AACR Genie 数据库，鉴定了 ROS1 酪氨酸激酶结构域中的 34 个错义突变进行进一步分析。我们的实验表明，这些突变对 ROS1 激酶功能有不同的影响，从完全丧失到显著增加的催化活性不等。值得注意的是，ROS1 激酶结构域中 Asp2113 上的 Asn 和 Gly 取代被发现是细胞模型系统中对 TKI 敏感的致癌变体。体内实验表明，ROS1 D2113N 诱导的肿瘤形成对克唑替尼和劳拉替尼敏感，这两种药物均为 FDA 批准的 ROS1-TKI。总之，这些发现强调了 ROS1 激酶结构域内特定点突变的致瘤潜力及其作为 FDA 批准的 ROS1-TKI 治疗靶点的潜力。
