Abstract 4294: SMCHD1 is a synthetic lethal strategy for cancers with a cancer-testis antigen gene expression signature

Abstract SMCHD1 is a component of the structural maintenance of chromosomes (SMC) protein family involved in epigenetic gene silencing of the X chromosome and other autosomal chromosome regions. SMCHD1 encodes an ATPase domain and binds chromatin at both N- and C-term domains to facilitate long-range chromatin interactions. However, the exact mechanism by which it elicits transcriptional silencing remains unknown. We have identified a selective dependency on SMCHD1 in cell lines exhibiting a gene expression signature characterized by high expression of multiple cancer testis antigen (CTA) genes. This CTA signature is observed in multiple cancers with >60% prevalence in Chronic Myeloid Leukemia. Importantly, SMCHD1’s effect on cell growth was independent of its ATPase activity, and a knock-in degron tag phenocopied SMCHD1 KO indicating that the proliferative advantage offered by SMCHD1 might be due to structural SMCHD1 function unrelated with its enzymatic ATPase role. Finally, SMCHD1 depletion led to the upregulation of multiple genes, including a cluster of CTA genes, in sensitive cell lines with the CTA-positive signature, while CTA-negative cell lines remained unaffected. These data confirm that SMCHD1 is a potential therapeutic target for patients with elevated CTA expression, and provides insight to what therapeutic modality would be most effective. Citation Format: Victor Quereda, Youyou Zhang, Diana Klimaszewska, Stefano Tonin, Theodore Groth, Yanhua Rao, Michael T. McCabe, Benjamin Schwartz, Markus Queisser, Rachel Buxton, Thomas J. Berrodin, Simon Peace. SMCHD1 is a synthetic lethal strategy for cancers with a cancer-testis antigen gene expression signature [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 4294.