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Published on: September 5, 2018
A Three-Dimensional Culture-Drug Sensitivity Test Predicts MDM2 Inhibitor-Sensitivity in SMARCB1/INI1-Deficient
Hiroaki Goto1,2, Chiyoko Nishime3, Takashi Ohtsu4,5
1Division of Hematology/Oncology, Kanagawa Children's Medical Center, Yokohama, Japan.
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.
Insights
This study shows that a 3D drug sensitivity test (3D-DST) can predict effective therapies for SMARCB1/INI1-deficient tumors. This personalized approach helps identify molecular targeting drugs for aggressive childhood cancers.
Area of Science:
- Oncology
- Cancer Biology
- Genetics
Background:
- Loss of SMARCB1/INI1 expression is a hallmark of aggressive pediatric tumors like malignant rhabdoid tumors.
- SMARCB1/INI1 deficiency causes widespread transcriptional changes, complicating targeted therapy development.
- Identifying effective treatments for these rare and aggressive cancers remains a significant challenge.
Purpose of the Study:
- To investigate the feasibility of personalized drug selection for SMARCB1/INI1-deficient tumors using in vitro drug sensitivity profiling.
- To evaluate the utility of a short-term collagen gel-embedded three-dimensional culture-drug sensitivity test (3D-DST) for this purpose.
Main Methods:
- Utilized cell line-derived mouse xenograft (CDX) models of SMARCB1/INI1-deficient tumors.
- Performed a short-term collagen gel-embedded 3D culture-drug sensitivity test (3D-DST) to assess drug responses.
- Analyzed gene expression and protein levels (TP53, p21) in response to drug treatment.
Main Results:
- The 3D-DST successfully identified potential molecular targeting drugs, including inhibitors of aurora B kinase, mTOR, MAPK, WNT/β-catenin, and MDM2.
- A CDX tumor resistant to MDM2 inhibitors showed lower TP53 expression compared to a sensitive tumor.
- MDM2 inhibitor treatment altered gene expression and induced p21 in sensitive cells, but not in resistant cells.
Conclusions:
- The 3D-DST is a valuable tool for predicting drug sensitivity in SMARCB1/INI1-deficient tumors.
- This in vitro method can guide the personalized selection of targeted therapies for these challenging cancers.
- The findings support the development of tailored treatment strategies based on individual tumor drug profiling.
