Outcomes are poor in patients with advanced or relapsed Ewing sarcoma (EWS) and current treatments have significant short- and long-term side effects. New, less toxic and more effective treatments are urgently needed. MER proto-oncogene tyrosine kinase (MERTK) promotes tumor cell survival, metastasis, and resistance to cytotoxic and targeted therapies in a variety of cancers.MERTKwas ubiquitously expressed in five EWS cell lines and five patient samples. Moreover, data from CRISPR-based library screens indicated that EWS cell lines are particularly dependent on MERTK. Treatment with MRX-2843, a first-in-class, MERTK-selective tyrosine kinase inhibitor currently in clinical trials, decreased the phosphorylation of MERTK and downstream signaling in a dose-dependent manner in A673 and TC106 cells and provided potent anti-tumor activity against all five EWS cell lines, with IC50values ranging from 178 to 297 nM. Inhibition of MERTK correlated with anti-tumor activity, suggesting MERTK inhibition as a therapeutic mechanism of MRX-2843. Combined treatment with MRX-2843 and BCL-2 inhibitors venetoclax or navitoclax provided enhanced therapeutic activity compared to single agents. These data highlight MERTK as a promising therapeutic target in EWS and provide rationale for the development of MRX-2843 for the treatment of EWS, especially in combination with BCL-2 inhibitors.
晚期或复发性尤文肉瘤（EWS）患者的预后较差，且现有治疗手段存在显著的短期与长期副作用。因此，亟需开发毒性更低、疗效更佳的新型治疗方案。MER原癌基因酪氨酸激酶（MERTK）在多种癌症中可促进肿瘤细胞存活、转移，并增强对细胞毒性及靶向治疗的耐药性。研究发现，MERTK在五种EWS细胞系及五例患者样本中普遍表达。基于CRISPR文库筛选的数据进一步表明，EWS细胞系对MERTK具有特异性依赖。使用目前处于临床试验阶段的首创MERTK选择性酪氨酸激酶抑制剂MRX-2843处理A673和TC106细胞，可剂量依赖性地降低MERTK及其下游信号通路的磷酸化水平，并对全部五种EWS细胞系均表现出显著的抗肿瘤活性，其IC50值介于178至297 nM之间。MERTK抑制程度与抗肿瘤活性呈正相关，提示MRX-2843通过抑制MERTK发挥治疗作用。与单药治疗相比，MRX-2843联合BCL-2抑制剂维奈托克或navitoclax可产生协同增效的抗肿瘤效果。这些研究结果揭示了MERTK作为EWS治疗靶点的重要潜力，并为开发MRX-2843（尤其是与BCL-2抑制剂联用）治疗EWS提供了理论依据。
肿瘤(癌症)患者之家