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...

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Autores principales:	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
Formato:	article
Lenguaje:	EN
Publicado:	BMC 2021
Materias:	Diffuse intrinsic pontine gliomas RG7388 p53 pathway Neurology. Diseases of the nervous system RC346-429
Acceso en línea:	https://doaj.org/article/e93641f3ec424b8eb9474f91fac10d50
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spelling	oai:doaj.org-article:e93641f3ec424b8eb9474f91fac10d502021-11-07T12:17:07ZTP53 wild-type/PPM1D mutant diffuse intrinsic pontine gliomas are sensitive to a MDM2 antagonist10.1186/s40478-021-01270-y2051-5960https://doaj.org/article/e93641f3ec424b8eb9474f91fac10d502021-11-01T00:00:00Zhttps://doi.org/10.1186/s40478-021-01270-yhttps://doaj.org/toc/2051-5960Abstract 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.Cheng XuHeng LiuChristopher J. PirozziLee H. ChenPaula K. GreerBill H. DiplasLiwei ZhangMatthew S. WaitkusYiping HeHai YanBMCarticleDiffuse intrinsic pontine gliomasRG7388p53 pathwayNeurology. Diseases of the nervous systemRC346-429ENActa Neuropathologica Communications, Vol 9, Iss 1, Pp 1-12 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Diffuse intrinsic pontine gliomas RG7388 p53 pathway Neurology. Diseases of the nervous system RC346-429
spellingShingle	Diffuse intrinsic pontine gliomas RG7388 p53 pathway Neurology. Diseases of the nervous system RC346-429 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
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.
format	article
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
title	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_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_sort	tp53 wild-type/ppm1d mutant diffuse intrinsic pontine gliomas are sensitive to a mdm2 antagonist
publisher	BMC
publishDate	2021
url	https://doaj.org/article/e93641f3ec424b8eb9474f91fac10d50
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TP53 wild-type/PPM1D mutant diffuse intrinsic pontine gliomas are sensitive to a MDM2 antagonist

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