SLFN11 is widely expressed in pediatric sarcoma and induces variable sensitization to 1 replicative stress caused by DNA damaging agents

Schlafen family member 11 (SLFN11) increases sensitivity to replicative stress and has been proposed as a biomarker to predict sensitivity to DNA damaging agents (DDA). However, the role of SLFN11 in pediatric cancer has not been well explored. In this study, we found that protein expression strongly correlated with response to the PARP inhibitor talazoparib and the topoisomerase I inhibitor irinotecan in sarcoma cell lines, with SLFN11 knockout resulting in significant loss of sensitivity in vitro and in vivo. However, in contrast to its activity in adult tumors, high SLFN11 expression did not correlate with favorable outcome in a retrospective study of children with sarcoma. Our work suggests that the potential of SLFN11 to act as a biomarker may be limited to certain tumor backgrounds or contexts, and that impaired apoptotic response may be one targetable mechanism of resistance to DDA-induced replicative stress We used microarrays to compare gene profiles expressed in the parental ES8 Ewings sarcoma cell line against profiles expressed in a derivative ES8 cell line (ES8-1F2)created by knockout of the human SLFN11 gene using CRISPR/Cas9. The parental ES8 cells and derivative ES8-SLFN-ko cells were treated with 0 Gy or 2 Gy irradiation, then RNA harvested at 4h or 24 h post-treatment.