TP53 wild-type/PPM1D mutant diffuse intrinsic pontine gliomas are sensitive to a MDM2 antagonist
Abstract Diffuse intrinsic pontine gliomas (DIPGs) are high-grade tumors of the brainstem that often occur in children, with a median overall survival of less than one year. Given the fact that DIPGs are resistant to chemotherapy and are not amenable to surgical resection, it is imperative to develo...
| Main Authors: | , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
BMC
2021-11-01
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| Series: | Acta Neuropathologica Communications |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s40478-021-01270-y |
| _version_ | 1818740048098492416 |
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| author | Cheng Xu Heng Liu Christopher J. Pirozzi Lee H. Chen Paula K. Greer Bill H. Diplas Liwei Zhang Matthew S. Waitkus Yiping He Hai Yan |
| author_facet | Cheng Xu Heng Liu Christopher J. Pirozzi Lee H. Chen Paula K. Greer Bill H. Diplas Liwei Zhang Matthew S. Waitkus Yiping He Hai Yan |
| author_sort | Cheng Xu |
| collection | DOAJ |
| description | Abstract Diffuse intrinsic pontine gliomas (DIPGs) are high-grade tumors of the brainstem that often occur in children, with a median overall survival of less than one year. Given the fact that DIPGs are resistant to chemotherapy and are not amenable to surgical resection, it is imperative to develop new therapeutic strategies for this deadly disease. The p53 pathway is dysregulated by TP53 (~ 60%) or PPM1D gain-of-function mutations (~ 30%) in DIPG cases. PPM1D gain-of-function mutations suppress p53 activity and result in DIPG tumorigenesis. While MDM2 is a major negative regulator of p53, the efficacy of MDM2 inhibitor has not been tested in DIPG preclinical models. In this study, we performed a comprehensive validation of MDM2 inhibitor RG7388 in patient-derived DIPG cell lines established from both TP53 wild-type/PPM1D-mutant and TP53 mutant/PPM1D wild-type tumors, as well in TP53 knockout isogenic DIPG cell line models. RG7388 selectively inhibited the proliferation of the TP53 wild-type/PPM1D mutant DIPG cell lines in a dose- and time-dependent manner. The anti-proliferative effects were p53-dependent. RNA-Seq data showed that differential gene expression induced by RG7388 treatment was enriched in the p53 pathways. RG7388 reactivated the p53 pathway and induced apoptosis as well as G1 arrest. In vivo, RG7388 was able to reach the brainstem and exerted therapeutic efficacy in an orthotopic DIPG xenograft model. Hence, this study demonstrates the pre-clinical efficacy potential of RG7388 in the TP53 wild-type/PPM1D mutant DIPG subgroup and may provide critical insight on the design of future clinical trials applying this drug in DIPG patients. |
| first_indexed | 2024-12-18T01:34:32Z |
| format | Article |
| id | doaj.art-e93641f3ec424b8eb9474f91fac10d50 |
| institution | Directory Open Access Journal |
| issn | 2051-5960 |
| language | English |
| last_indexed | 2024-12-18T01:34:32Z |
| publishDate | 2021-11-01 |
| publisher | BMC |
| record_format | Article |
| series | Acta Neuropathologica Communications |
| spelling | doaj.art-e93641f3ec424b8eb9474f91fac10d502022-12-21T21:25:31ZengBMCActa Neuropathologica Communications2051-59602021-11-019111210.1186/s40478-021-01270-yTP53 wild-type/PPM1D mutant diffuse intrinsic pontine gliomas are sensitive to a MDM2 antagonistCheng Xu0Heng Liu1Christopher J. Pirozzi2Lee H. Chen3Paula K. Greer4Bill H. Diplas5Liwei Zhang6Matthew S. Waitkus7Yiping He8Hai Yan9Department of Pathology, Duke UniversityDepartment of Pathology, Duke UniversityDepartment of Pathology, Duke UniversityDepartment of Pathology, Duke UniversityDepartment of Pathology, Duke UniversityDepartment of Radiation Oncology, Memorial Sloan Kettering Cancer CenterDepartment of Neurosurgery, Beijing Tiantan Hospital, Capital Medical UniversityPreston Robert Tisch Brain Tumor Center, Duke University Medical CenterDepartment of Pathology, Duke UniversityDepartment of Pathology, Duke UniversityAbstract Diffuse intrinsic pontine gliomas (DIPGs) are high-grade tumors of the brainstem that often occur in children, with a median overall survival of less than one year. Given the fact that DIPGs are resistant to chemotherapy and are not amenable to surgical resection, it is imperative to develop new therapeutic strategies for this deadly disease. The p53 pathway is dysregulated by TP53 (~ 60%) or PPM1D gain-of-function mutations (~ 30%) in DIPG cases. PPM1D gain-of-function mutations suppress p53 activity and result in DIPG tumorigenesis. While MDM2 is a major negative regulator of p53, the efficacy of MDM2 inhibitor has not been tested in DIPG preclinical models. In this study, we performed a comprehensive validation of MDM2 inhibitor RG7388 in patient-derived DIPG cell lines established from both TP53 wild-type/PPM1D-mutant and TP53 mutant/PPM1D wild-type tumors, as well in TP53 knockout isogenic DIPG cell line models. RG7388 selectively inhibited the proliferation of the TP53 wild-type/PPM1D mutant DIPG cell lines in a dose- and time-dependent manner. The anti-proliferative effects were p53-dependent. RNA-Seq data showed that differential gene expression induced by RG7388 treatment was enriched in the p53 pathways. RG7388 reactivated the p53 pathway and induced apoptosis as well as G1 arrest. In vivo, RG7388 was able to reach the brainstem and exerted therapeutic efficacy in an orthotopic DIPG xenograft model. Hence, this study demonstrates the pre-clinical efficacy potential of RG7388 in the TP53 wild-type/PPM1D mutant DIPG subgroup and may provide critical insight on the design of future clinical trials applying this drug in DIPG patients.https://doi.org/10.1186/s40478-021-01270-yDiffuse intrinsic pontine gliomasRG7388p53 pathway |
| spellingShingle | Cheng Xu Heng Liu Christopher J. Pirozzi Lee H. Chen Paula K. Greer Bill H. Diplas Liwei Zhang Matthew S. Waitkus Yiping He Hai Yan TP53 wild-type/PPM1D mutant diffuse intrinsic pontine gliomas are sensitive to a MDM2 antagonist Acta Neuropathologica Communications Diffuse intrinsic pontine gliomas RG7388 p53 pathway |
| title | TP53 wild-type/PPM1D mutant diffuse intrinsic pontine gliomas are sensitive to a MDM2 antagonist |
| title_full | TP53 wild-type/PPM1D mutant diffuse intrinsic pontine gliomas are sensitive to a MDM2 antagonist |
| title_fullStr | TP53 wild-type/PPM1D mutant diffuse intrinsic pontine gliomas are sensitive to a MDM2 antagonist |
| title_full_unstemmed | TP53 wild-type/PPM1D mutant diffuse intrinsic pontine gliomas are sensitive to a MDM2 antagonist |
| title_short | TP53 wild-type/PPM1D mutant diffuse intrinsic pontine gliomas are sensitive to a MDM2 antagonist |
| title_sort | tp53 wild type ppm1d mutant diffuse intrinsic pontine gliomas are sensitive to a mdm2 antagonist |
| topic | Diffuse intrinsic pontine gliomas RG7388 p53 pathway |
| url | https://doi.org/10.1186/s40478-021-01270-y |
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