Identifying the druggable interactome of EWS-FLI1 reveals MCL-1 dependent differential sensitivities of Ewing sarcoma cells to apoptosis inducers

The cover for issue 57 of Oncotarget features Figure 1A, "Schematic representation of our systematic approach developed to identify effective compounds and biological vulnerabilities in EwS.," by Tsafou, et al.

The research group identified differential sensitivities of Ewing sarcoma cells to BCL-2 family inhibitors dependent on the EWS-FLI1 regulome including altered MCL-1 expression and subcellular localization. This study facilitates the selection of effective targeted approaches for future combinatorial therapies of patients suffering from Ewing sarcoma.

Dr. Heinrich Kovar from the Children's Cancer Research Institute, St. Anna Kinderkrebsforschung, Vienna, Austria and the Department of Pediatrics, Medical University of Vienna, Vienna, Austria said, "Ewing sarcoma belongs to a family of highly malignant primary tumors, which arise in bone and soft tissues, affecting children and adolescents."

Depending on their BCL-2 homology domains and function, the BCL-2 family of proteins can be classified into three different groups. The pro-apoptototic BCL-2 family members, BAX and BAK, anti-apoptotic members BCL-2, MCL-1, BCL-X, BCL-W and BFL-1/A1. Via alternative splicing the long isoform of anti-apopototic BCL-2 family member proteins can be shortened into a pro-apoptotic version, such as for MCL-1 and BCL-X, further influencing the balance between pro- and antiapoptotic proteins within a cell.

Figure 1: Compound and target discovery. (A) Schematic representation of our systematic approach developed to identify effective compounds and biological vulnerabilities in EwS. (B) Distribution of targets per compound. Left: Target distribution of the effective compounds (hits). The effective compounds with known targets included 23 experimental and 47 FDA approved compounds. FDA approved drugs cover the major percentage of the 70 hits (67%), and the median of the reported targets is 4. Right: Target distribution of the non-effective compounds. The median of targets for the non-effective compounds (with at least one known target) is 5 and the list includes 27% (394) FDA approved compounds.

Given the importance of BCL-2 proteins for oncogenic cell survival, several BCL-2 family inhibitors, so called BH3 mimetics, have been developed. Investigation of BCL-2 family member protein expression and their subcellular localization revealed an EWS-FLI1 dependent effect on MCL-1 to be at least partially responsible for the differential sensitivities of Ew S cells towards navitoclax treatment.

The Heinrich Kovar research team concluded, "In addition, we provide a list of compounds not effective in any of the conditions tested but also a list of compounds effective in both EWS-FLI1-high and -low cells that could inform and accelerate the progress of future Ew S therapeutic strategies."

Full text - https://doi.org/10.18632/oncotarget.25760

Correspondence to - Heinrich Kovar - heinrich.kovar@ccri.at

Keywords - high-throughput compound screening, Ewing sarcoma, drug-target network, apoptosis, BCL-2 inhibitors