Targeting the CHD3 chromatin remodeler exploits a synthetic lethal vulnerability in dual SMARCA4/SMARCA2-deficient cancers via derepression of PARD3B

While SMARCA2 paralog-targeting strategies exist for single-subunit loss of SMARCA4, dual SMARCA4/SMARCA2-deficient tumors lack actionable targets. Here, we identify the CHD3/NuRD nucleosome remodeling complex as a critical synthetic lethal vulnerability in these malignancies.

Through integrated genomic analyses, we demonstrate that in the absence of SWI/SNF, CHD3 acts as an essential “epigenetic brake” specifically at the enhancer of the cell polarity regulator PARD3B. Loss of CHD3 triggers aberrant chromatin hyper-accessibility and toxic derepression of PARD3B. We further elucidate that PARD3B accumulation is a critical mediator of cell death, which is strongly associated with the attenuation of MYC signaling signatures.