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

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.