EZH1/2 inhibition selectively targets SMARCA4/2 co-deficient lung cancer cells by suppressing stemness and proliferation

作者：Jeongjae Lee, Jaeik Oh, Soyeon Kim, Taekeun Park, Jeonghwan Youk, Miso Kim, Tae Min Kim, Dong‐Wan Kim, Bhumsuk Keam · 发表于：Neoplasia · 年份：2026 · DOI：10.1016/j.neo.2026.101349 · 研究领域：Chromatin Remodeling and Cancer、Mechanisms of cancer metastasis、Genomics and Rare Diseases

SMARCA4-deficient thoracic malignancies comprise biologically heterogeneous tumors, ranging from conventional non-small cell lung cancer with SMARCA4 alterations to thoracic SMARCA4-deficient undifferentiated tumor (SMARCA4-UT), an aggressive entity frequently associated with concomitant SMARCA2 loss. However, the extent to which SMARCA4-deficient lung cancer cell lines recapitulate SMARCA4-UT-like biology remains incompletely defined. Here, we characterized lung cancer cell lines across distinct SMARCA4 and SMARCA2 states and identified a subgroup with SMARCA4/2 co-deficiency that exhibited reduced expression of epithelial lineage markers and transcriptional similarity to SMARCA4-UT and other SWI/SNF-deficient malignancies. The EZH1/2 inhibitor HM97662 selectively suppressed growth in SMARCA4/2-deficient cells, with limited effects in SMARCA2-proficient cells. EZH1/2 inhibition broadly reduced H3K27me3 and induced derepression of PRC2 targets regardless of drug sensitivity. However, its biological effects were most pronounced in SMARCA4/2-deficient cells, where it promoted apoptosis, reduced stemness marker expression, attenuated the SMARCA4-UT-associated transcriptional signature, and suppressed proliferative and mTORC1-related programs. Chromatin accessibility analysis further revealed cell-line-specific patterns of accessibility loss, with reduced accessibility at stemness-associated transcription factor motif-enriched regions coupled with transcriptional repression of ne...