Synergistic targeting of EP300/CBP and EYA co-activators collapses the rhabdomyosarcoma core regulatory circuit. [ChIP-Seq]

These mTFs are regulated by super-enhancers, and they co-bind genome-wide to control the malignant transcriptome of both FP- and FN-RMS. Using a super-enhancer-based reporter screen, we identify the EP300/CBP inhibitor A485 as a potent inhibitor of the pan-RMS CRC, though efficacy of this compound was limited by toxicity. To enhance on-target specificity, we identify the protein EYA2 as a co-factor of the pan-RMS CRC, and use a second-generation EYA1/2 tyrosine phosphatase inhibitor called LG1-34 to inactivate its function.

While A485 and LG1-34 independently reduce mTF transcription and drive RMS cell death, in combination, these agents function synergistically to reduce RMS growth in vitro and in vivo. These results demonstrate that combined targeting of enhancer maintenance and CRC co-factors is a powerful strategy to suppress the RMS transcriptome and enforce RMS cell death.