Biology and Therapy of Dominant Fusion Oncoproteins Involving Transcription Factor and Chromatin Regulators in Sarcomas

Abstract

A third of soft tissue sarcomas have been shown to carry recurrent, characteristic chromosomal translocations, many of which generate fusion proteins that act as dominant transcription factors or as chromatin regulators. With routine use of massively parallel sequencing and advances in technology for the study of epigenetics and protein complexes, the last decade has seen a marked advancement in the identification of novel fusions and in our understanding of the mechanisms by which they contribute to the malignant state. Moreover, with new approaches in chemistry, such as the strategy of targeted protein degradation, we are now better poised to address these previously intractable targets. In this review, we describe three of the most common fusion-driven sarcomas (Ewing sarcoma, alveolar rhabdomyosarcoma, and synovial sarcoma), mechanistic themes emerging across these diseases, and novel approaches to their targeting.