Elimusertib enhances cytotoxic effects of conventional chemotherapy and sensitizes to radiation in preclinical Ewing sarcoma models

Ewing Sarcoma (EwS) is a highly aggressive malignancy predominantly affecting young individuals, with poor prognosis in metastatic or relapsed cases. This study investigates the therapeutic potential of ataxia telangiectasia and Rad3-related protein (ATR) inhibition using the selective small-molecule inhibitor elimusertib, both as a monotherapy and in combination with cytotoxic drugs or radiotherapy. Elimusertib significantly inhibited cell proliferation and induced apoptosis in EwS cell lines. In a chorioallantoic membrane (CAM) model, elimusertib suppressed tumor initiation and reduced tumor volume. Notably, elimusertib exhibited synergistic effects with standard chemotherapeutics and radiation, enhancing antitumor efficacy. These preclinical findings suggest that ATR inhibition by elimusertib may enhance current EwS therapies and enable dose reduction of cytotoxic drugs. Further clinical evaluation is warranted to validate these findings and explore elimusertib’s translational potential in EwS treatment.