Smart Sherri K, Yeung Tsz Y, Santos M Olivia, McSwain Leon F, Wang Xiaodong, Frye Stephen V, Earp H Shelton, DeRyckere Deborah, Graham Douglas K
Aflac Cancer and Blood Disorders Center, Children's Healthcare of Atlanta, Atlanta, GA 30322, USA.
Department of Pediatrics, Emory University School of Medicine, Atlanta, GA 30322, USA.
Cancers (Basel). 2024 Aug 12;16(16):2831. doi: 10.3390/cancers16162831.
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. was 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 IC values 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.
晚期或复发性尤因肉瘤（EWS）患者的预后较差，且目前的治疗方法存在显著的短期和长期副作用。迫切需要新的、毒性更小且更有效的治疗方法。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、转移以及对细胞毒性和靶向治疗的抗性。其在五种EWS细胞系和五个患者样本中均有广泛表达。此外，基于CRISPR文库筛选的数据表明，EWS细胞系对MERTK尤为依赖。目前正处于临床试验阶段的首个MERTK选择性酪氨酸激酶抑制剂MRX-2843，在A673和TC106细胞中以剂量依赖性方式降低了MERTK的磷酸化及下游信号传导，并对所有五种EWS细胞系均具有强大的抗肿瘤活性，IC值范围为178至297 nM。抑制MERTK与抗肿瘤活性相关，提示MERTK抑制是MRX-2843的治疗机制。与单药治疗相比，MRX-2843与BCL-2抑制剂维奈克拉或纳维托克司联合治疗具有更强的治疗活性。这些数据凸显了MERTK作为EWS中有前景的治疗靶点，并为开发MRX-2843用于治疗EWS提供了理论依据，尤其是与BCL-2抑制剂联合使用时。
