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Significance Oncogenic transcription factors, such as the CIC-DUX4 fusion protein, constitute cancer-specific but highly challenging therapeutic targets. Consequently, pharmacologic targeting of transcription factor fusions has relied on identifying downstream actionable targets that relay fusion protein function. While informative, this approach has been limited by the divergent pleotropic effects of transcription factor fusion output. To overcome this, we have developed a mechanism-based strategy to directly degrade the CIC-DUX4 oncoprotein through ligand-dependent or pharmacologic MAPK activation. Using small-molecule drugs that block negative regulators of MAPK-ERK signaling, such as DUSP6, we reveal MAPK-mediated CIC-DUX4 degradation as an innovative therapeutic approach to targeting CIC-fused sarcoma.

Negative MAPK-ERK regulation sustains CIC-DUX4 oncoprotein expression in undifferentiated sarcoma