SLFN11 Modulation by CRISPR/dCas9 in Pediatric Cancer Cells Affects Toxicity of DNA Damaging Agents

The highly conserved mammalian nuclear protein Schlafen 11 (SLFN11) has been of great interest in the field of cancer therapeutics since its expression has been found to correlate with sensitivity to DNA damaging agents. Building upon its established significance in adult cancers, this study investigates the predictive value and functional role of SLFN11 in pediatric tumors. In-silico analysis reveals varying patterns of SLFN11 expression in pediatric tumors, and different overall survival outcomes in high SLFN11 tumors, contrasting with adult tumor literature. We explored two methods for enhancing SLFN11 expression. Initially, we sought to utilize Decitabine (DAC) to demethylate the SLFN11 promoter; as expected from our experience with the adult cancer setting, this strategy showed minimal success. Consequently, we shifted our focus to the use of CRISPR activation. The CRISPRdCas9 - UNISAM system was used to upregulate SLFN11 in pediatric cancer cells, resulting in an increased sensitivity to therapeutic agents such as cisplatin and talazoparib. Our findings shed light on SLFN11's potential as a therapeutic target or predictive biomarker in pediatric cancers, emphasizing the need for further research into SLFN11's role and therapeutic potential, with implications for precision oncology approaches.