| Autor: |
Smart SK; 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., Yeung TY; 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., Santos MO; Duke University School of Medicine, Durham, NC 27710, USA., McSwain LF; 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., Wang X; Center for Integrative Chemical Biology and Medicinal Chemistry, UNC Eshelman School of Pharmacy, Chapel Hill, NC 27599, USA., Frye SV; Center for Integrative Chemical Biology and Medicinal Chemistry, UNC Eshelman School of Pharmacy, Chapel Hill, NC 27599, USA.; UNC Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA., Earp HS 3rd; UNC Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.; Departments of Medicine and Pharmacology, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA., DeRyckere D; 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., Graham DK; 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. |
| Abstrakt: |
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. MERTK 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 50 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. |
