Core transcriptional regulatory circuitry identified from patient-derived tumor cells provides a specific vulnerability for rhabdomyosarcoma

Abstract Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma in children and adolescents, with limited targeted treatment options. Core transcriptional regulatory circuitry (CRC) proteins play crucial roles in tumor cell identity and survival. Here, we established 15 patient-derived tumor cells (PDCs) from RMS specimens and found that these cells retained the expression of RMS hallmark and dependency genes, as well as the genetic mutations in primary tumors. Cleavage under targets and tagmentation sequencing (CUT&Tag-seq) for H3K27ac in these RMS PDCs identified super-enhancers and the associated CRC, which contained SMAD3, RUNX2, JUN and FOS. These factors formed an interconnected auto-regulatory loop that maintained the malignant cell state in RMS. Knocking down each of these genes decreased the expression of all the CRC members and impaired tumor cell growth in RMS. CDK7 inhibition by THZ1 disrupted the CRC and effectively suppressed cell proliferation in RMS. Our study demonstrates a common CRC in RMS that is essential for tumor maintenance, providing a promising therapeutic vulnerability for RMS.