Abstract B005: Synergistic targeting of EP300/CBP and EYA co-activators collapses the rhabdomyosarcoma core regulatory circuit

Abstract

Rhabdomyosarcoma (RMS) is a high-risk pediatric sarcoma that resembles developing skeletal muscle. Transcriptional dysregulation drives RMS pathogenesis in tumors carrying chimeric transcription factors (“fusion-positive (FP)”), and those without (“fusion-negative” (FN)). Here, we develop a novel approach against RMS-specific transcription programs with multiple small molecules targeting multiple pieces of transcription apparatus. We identify a pan-RMS core regulatory circuit (CRC) composed of super-enhancer regulated master transcription factors (mTFs) that cobind genome-wide to drive the transcriptome of FP- and FN-RMS. Using a super-enhancer-based reporter screen, we identify the EP300/CBP inhibitor A485 as a potent CRC inhibitor. To enhance specificity, we uncover EYA2 as a CRC co-factor and use an EYA1/2 tyrosine phosphatase inhibitor, LG1-34, to inactivate its function. While A485 and LG1-34 independently reduce mTF transcription and drive RMS cell death, combined, these agents synergistically reduce RMS growth in vitro and in vivo. Combined targeting of enhancer maintenance and CRC cofactors is a powerful strategy to suppress the RMS transcriptome and enforce RMS death.