Abstract 3990: MERTK is a potential therapeutic target in Ewing sarcoma

Abstract

Abstract Ewing sarcoma (EWS) is the second most common pediatric bone tumor, and outcomes remain poor in patients with advanced or relapsed disease. In addition, current treatments rely on multi-modal therapy that has significant short- and long-term side effects. New, less toxic and more effective treatments are urgently needed. One potential therapeutic target is the receptor tyrosine kinase MERTK. MERTK is overexpressed in numerous cancers where it promotes tumor cell survival, metastasis, and resistance to cytotoxic and targeted therapies. We demonstrated expression and phosphorylation of MERTK protein in 5 of 5 EWS family cell lines tested. Stimulation with the MERTK ligand GAS6 resulted in activation of downstream oncogenic signaling pathways, including JAK/STAT and MAPK/ERK. Moreover, publicly available data from CRISPR-based library screens suggest that EWS cell lines are particularly dependent on MERTK. Thus, therapeutic strategies targeting MERTK may be particularly effective for treatment of EWS. To explore the therapeutic impact of MERTK inhibition in various cancers, we developed MRX-2843, a first-in-class MERTK-selective tyrosine kinase inhibitor that is currently in clinical trials. Treatment with MRX-2843 decreased phosphorylation of MERTK in a dose dependent manner, with an IC50 of 123 nM (95% CI; 53-180 nM) in A673 cells, and reduced downstream STAT6 signaling. In addition, MRX-2843 had potent anti-tumor activity against all 5 EWS cell lines, leading to reduced expansion and decreased cell density in culture with IC50 values ranging from 178 - 297 nM. Of note, inhibition of MERTK phosphorylation correlated with anti-tumor activity in both the A673 and TC106 cell lines, implicating MERTK inhibition as a mechanism of MRX-2843 anti-tumor activity. Together these data validate MERTK as a promising therapeutic target in EWS and support development of MRX-2843 for treatment of EWS, with potential to directly inform and enable a clinical trial in pediatric patients and, ultimately, to improve both outcomes and quality of life for patients with this disease. Citation Format: Sherri K. Smart, Tsz Y. Yeung, Xiaodong Wang, Stephen V. Frye, H. Shelton Earp, Douglas K. Graham, Deborah DeRyckere. MERTK is a potential therapeutic target in Ewing sarcoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3990.