Synergistic Effects of ATR Inhibition and Lurbinectedin in Soft-Tissue Sarcomas: The Predictive Role of SLFN11 Expression.

Purpose: To evaluate the synergistic effects of lurbinectedin combined with ataxia telangiectasia and Rad3-related (ATR) inhibition in the treatment of soft-tissue sarcomas (STS) and investigate the predictive value of Schlafen-11 (SLFN11) expression in determining treatment response.

Experimental Design: Fourteen STS cell lines were treated with lurbinectedin, the ATR inhibitor VE-822, and their combination. Cytotoxicity was assessed using cell viability assays, γ-H2AX immunostaining, cell-cycle analysis, and apoptosis assays. SLFN11 expression was modulated using CRISPR-Cas9, and its role in treatment response was analyzed. In vivo efficacy was evaluated using a patient-derived xenograft model of undifferentiated pleomorphic sarcoma.

Results: The combination of lurbinectedin and VE-822, also known as berzosertib, showed synergistic cytotoxicity in STS cell lines, significantly enhancing DNA damage and inducing apoptosis and cell-cycle arrest. SLFN11 expression correlated with sensitivity to lurbinectedin, and CRISPR-mediated SLFN11 knockdown confirmed its role in modulating treatment response. Low SLFN11 expression was associated with reduced synergy between lurbinectedin and berzosertib. In vivo, the combination treatment significantly inhibited tumor growth compared with either agent alone, without observed toxicity.

Conclusions: This study highlights the potential of combining lurbinectedin with ATR inhibitors in STS treatment and validates SLFN11 as a predictive biomarker for this combination therapy. These findings support further clinical evaluation of this therapeutic strategy in patients with STS.