FusionPathway: Prediction of pathways and therapeutic targets associated with gene fusions in cancer

Numerous gene fusions have been uncovered across multiple cancer types. Although the ability to target several of these fusions has led to the development of some successful anti-cancer drugs, most of them are not druggable. Understanding the molecular pathways of a fusion is important in determining its function in oncogenesis and in developing therapeutic strategies for patients harboring the fusion. However, the molecular pathways have been elucidated for only a few fusions, in part because of the labor-intensive nature of the required functional assays. Therefore, we developed a domain-based network approach to infer the pathways of a fusion. Molecular interactions of a fusion are first predicted by using its protein domain composition, and its associated pathways are then inferred from these molecular interactions. We demonstrated the capabilities of this approach by primarily applying it to the well-studied BCR-ABL1 fusion. The approach was also applied to two undruggable fusions in sarcoma, EWS-FL1 and FUS-DDIT3. We successfully identified known genes and pathways associated with these fusions and satisfactorily validated these predictions using several benchmark sets. The predictions of EWS-FL1 and FUS-DDIT3 also correlate with results of high-throughput drug screening. To our best knowledge, this is the first approach for inferring pathways of fusions.