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A Three‐Dimensional Culture–Drug Sensitivity Test Predicts MDM2 Inhibitor–Sensitivity in SMARCB1 / INI1 ‐Deficient Tumors

Year: 2026

Type: article

Abstract: Loss of SMARCB1/INI1 expression is a common feature of various types of tumors including malignant rhabdoid tumor, an aggressive cancer of children. Because SMARCB1/INI1 deficiency leads to genome-wide transcriptional dysregulation, identifying a specific therapeutic target that acts on a wide range of SMARCB1/INI1-deficient tumors has been challenging. This study aimed to establish if the personalized selection of effective drugs against SMARCB1/INI-deficient tumors is possible by in vitro drug sensitivity profiling. The in vitro drug sensitivity profiles of tumors from SMARCB1/INI1-deficient tumor cell line-derived mouse xenograft (CDX) models were evaluated by a short-term collagen gel-embedded three-dimensional culture-drug sensitivity test (3D-DST). With the 3D-DST, molecular targeting drugs, including inhibitors of aurora B kinase, mammalian target of rapamycin, mitogen-activated protein kinase, WNT/β-catenin, or mouse double minute 2 homolog (MDM2), were selected as therapeutic drug candidates in SMARCB1/INI1-deficient tumors. A CDX tumor, which was resistant to MDM2 inhibitors in the 3D-DST, expressed lower TP53 compared to an MDM2 inhibitor-sensitive tumor. In cultured cell lines, exposure to MI-773, a MDM2 inhibitor, disturbed the expression of a significant number of genes and induced p21 protein expression in MDM2 inhibitor-sensitive cells. However, such changes were not observed in resistant cells. These results suggest that 3D-DST can predict biologically relevant drug sensitivity profiles in SMARCB1/INI1-deficient tumors.

Source: Cancer Science

DOI: 10.1111/cas.70451