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

SWI/SNF-deficient cancers characterized by dual SMARCA4/SMARCA2 loss, including subsets of lung adenocarcinoma and small cell carcinoma of the ovary, hypercalcemic type, represent a major therapeutic challenge. 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. This attenuation likely arises from the spatial perturbation of upstream signaling hubs or secondary cellular responses, reducing MYC transcriptional output without degrading the protein itself. Therapeutically, CHD3 depletion led to robust tumor regression in dual SMARCA4/SMARCA2-deficient xenografts, validating the in vivo mechanism of PARD3B upregulation. Collectively, our study defines a novel mode of synthetic lethality driven by "gain-of-toxicity" rather than the loss of survival signals, uncovering a fatal cross-complex dependency. We propose that targeting CHD3 to trigger toxic PARD3B derepression offers a promising therapeutic avenue for treatment-refractory dual SMARCA4/SMARCA2-deficient cancers.