Catalytic-independent functions of the Integrator-PP2A complex (INTAC) confer sensitivity to BET inhibition.

Chromatin and transcription regulators are critical to defining cell identity through shaping epigenetic and transcriptional landscapes, with their misregulation being closely linked to oncogenesis. Pharmacologically targeting these regulators, particularly the transcription-activating BET proteins, has emerged as a promising approach in cancer therapy, yet intrinsic or acquired resistance frequently occurs, with poorly understood mechanisms. Here, using genome-wide CRISPR screens, we find that BET inhibitor efficacy in mediating transcriptional silencing and growth inhibition depends on the auxiliary/arm/tail module of the Integrator-PP2A complex (INTAC), a global regulator of RNA polymerase II pause-release dynamics. This process bypasses a requirement for the catalytic activities of INTAC and instead leverages direct engagement of the auxiliary module with the RACK7/ZMYND8-KDM5C complex to remove histone H3K4 methylation. Targeted degradation of the COMPASS subunit WDR5 to attenuate H3K4 methylation restores sensitivity to BET inhibitors, highlighting how simultaneously targeting coordinated chromatin and transcription regulators can circumvent drug-resistant tumors.