Targeting the CHD3 Chromatin Remodeler Exploits a Synthetic Lethal Vulnerability in SWI/SNF- Deficient Cancers via Toxic Derepression of PARD3B

Abstract SWI/SNF-deficient cancers characterized by dual SMARCA4/SMARCA2 loss, including undifferentiated thoracic sarcomas and subsets of lung adenocarcinoma, represent a major therapeutic challenge. While paralog-targeting strategies exist for single-subunit loss, dual-deficient tumors lack actionable targets. Here, we identify the CHD3/NuRD nucleosome remodeling complex as a critical synthetic lethal vulnerability in these malignancies. Through an integrated genomic analysis, we demonstrate that in the absence of SWI/SNF, CHD3 acts as an essential "epigenetic brake" 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 drives cell death by inducing the "functional uncoupling" of MYC signaling. This occurs via spatial perturbation of upstream signaling hubs, which silences MYC transcriptional output without degrading the protein itself. Therapeutically, CHD3 depletion led to robust tumor regression in SWI/SNF-deficient xenografts, validating the mechanism of PARD3B upregulation and the collapse of the MYC pathway in vivo. Our study defines a novel mode of synthetic lethality driven by "gain-of-toxicity" rather than loss of survival signals, uncovering a fatal cross-complex dependency. We propose that targeting CHD3 to unleash PARD3B toxicity offers a promising therapeutic avenue for treatment-refractory SWI/SNF-deficient cancers.