Synergistic targeting of EP300/CBP and EYA co-activators collapses the rhabdomyosarcoma core regulatory circuit
Gustafson, A. L.; Nance, S.; Gryder, B.; Shendy, N. A. M.; Wick, L.; McKay-Corkum, G.; Ritter, K. E.; Purdy, S. C.; Wolin, A. R.; Rosenbaum, S. R.; Mathavarajah, S.; Demelfi, N. A.; Wang, Y.; Zhang, Y.; Zimmerman, M.; Kavirayani, A.; Citarella, E. A.; Ebegboni, V. J.; Hardin, J. W.; LaVeck, A.; Wang, X.; Dharia, N.; Hong, A. L.; Kugener, G.; Boehm, J. S.; Roth, J. A.; Khan, J.; Vazquez, F.; Artinger, K.; Zhao, R.; Langenau, D. M.; Qi, J.; Stegmaier, K.; Abraham, B.; Ford, H.; Durbin, A. D.
Show abstract
Rhabdomyosarcoma (RMS) is a multi-subtype, high-risk pediatric sarcoma with a low mutational burden. The mutations found in RMS often alter genes involved in transcriptional control. Approaches to target dysregulated RMS transcription have remained elusive. Here, we develop a novel approach to target RMS transcription comprising simultaneous targeting of two distinctly acting transcriptional co-activators. We discover a common identity-controlling pan-RMS core regulatory circuit (CRC) composed of oncogenic and lineage-specific myogenic master transcription factors (mTFs). Using a super-enhancer-based reporter screen, we identify the EP300/CBP inhibitor A485 as a potent inhibitor of the pan-RMS CRC, though with efficacy-limiting toxicities. To enhance efficacy, we identify the mTF-binding co-activator EYA2 as a co-factor of this pan-RMS CRC and exploit a new second-generation EYA1/2 inhibitor, LG1-34, to disrupt its function. Combined co-activator inhibition inactivates the CRC and synergistically reduces RMS growth. This strategy dually targets CRC-associated co-activators to cooperatively suppress the RMS transcriptome and enforce cell death.
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