Pre-clinical optimization of MDM2 antagonist treatment of glioblastoma
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE291870 | GEO | 2026/03/31
REPOSITORIES: GEO
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Project description:Malignant rhabdoid tumors (MRT) are highly aggressive pediatric cancers that respond poorly to current therapies. We screened several MRT cell lines each with large-scale RNAi, CRISPR-Cas9, and small-molecule libraries to identify potential drug targets specific for these cancers. We discovered MDM2 and MDM4, the canonical negative regulators of p53, as significant vulnerabilities. Using two compounds currently in clinical development, idasanutlin and ATSP-7041, we show that MRT cells are more sensitive than other p53 wild-type cancer cell lines to MDM2 and dual MDM2/4 inhibition in vitro. These compounds cause significant upregulation of the p53 pathway in MRT cells, and sensitivity is ablated by CRISPR-Cas9-mediated inactivation of TP53. We show that loss of SMARCB1, a subunit of the SWI/SNF (BAF) complex mutated in nearly all MRT, sensitizes cells to MDM2 and MDM2/4 inhibition by enhancing p53-mediated apoptosis. Both MDM2 and MDM2/4 inhibition slowed MRT xenograft growth in vivo, with a five-day idasanutlin pulse causing marked regression of all xenografts including durable complete responses in 50% of mice. Together, these studies identify a genetic connection between mutations in the SWI/SNF chromatin-remodeling complex and the tumor suppressor gene p53, and provide preclinical evidence to support the targeting of MDM2 and MDM4 in this often-fatal pediatric cancer.
2019-02-04 | GSE124508 | GEO
Project description:The E3 ligase MDM2 promotes tumor growth and progression by inducing ubiquitin-mediated degradation of P53 and other tumor suppressing proteins. Here, we identified an MDM2-interacting lncRNA NRON, which promotes tumor formation by suppressing both P53-dependent and independent pathways. NRON binds to MDM2 and MDMX (MDM4) via two different stem-loops respectively and induces their heterogenous dimerization, thereby enhancing the E3 ligase activity of MDM2 towards its tumor suppressing substrates, including P53, RBI and NFATI, etc.
2023-06-19 | GSE226511 | GEO
Project description:The aim of this experiment has been to investigate the transcriptional profile of HCT116 cells treated with Peptide-3 (Pep3) compared to untreated (NT), treated with solvent (DMSO) or with a mutated peptide (Pep3M) cells. Peptide-3 is a dodecapeptide able to interact with MDM2 at the levels of the interaction region of the MDM4 and MDM2 proteins, thereby interfering with the coopeartivy function of the proteins in the regulation of p53. This peptide is indeed able to specifically activate p53 and to cause apoptotis in different cancer cell lines and tumor growth inhibition in xenograft models.
2017-04-18 | GSE62855 | GEO
Project description:CDK4 inhibitors have reached clinical approval for cancer therapy. In parallel, the p53 antagonist Mdm2 remains an attractive target for anti-cancer therapy, including numerous clinical studies. The genes encoding Mdm2 and CDK4 are frequently co-amplified in human malignancies, most notably in liposarcomas, suggesting their combined targeting for therapy. Here we show, however, that small compounds that inhibit Mdm2 and CDK4 antagonize each other rather than synergize in their cytotoxicity towards sarcoma cells. CDK4 inhibition attenuates the induction of p53-responsive genes upon Mdm2 inhibition, and similar results were obtained when depleting Mdm2 and/or CDK4 with siRNA. CDK4 inhibitors also interfered with p53 activity in response to DNA damage. CDK4 inhibition did not reduce p53 binding or histone acetylation to promoters, but rather attenuated the subsequent recruitment of RNA polymerase II. The complexes of p53 and Mdm2, as well as CDK4 and Cyclin D1, physically associated with each other. Upon combined inhibition of Mdm2 and CDK4/6, the interaction of this complex was impaired. Thus, the CDK4-Cyclin D1 complex plays a key role in enabling the transcription of p53 target genes. Taken together, our results raise caution regarding the combination of CDK4 inhibitors with Mdm2 antagonists or conventional DNA-damaging chemotherapeutics in the clinics. Moreover, they suggest a hitherto unknown role for CDK4-cyclin D1 complex in sustaining p53 activity, possibly focusing p53-mediated transcription on actively proliferating cells.
2018-09-20 | GSE113369 | GEO
Project description:The aim of this experiment has been to investigate the transcriptional profile of HCT116 cells treated with Peptide-3 (Pep3) compared to untreated (NT), treated with solvent (DMSO) or with a mutated peptide (Pep3M) cells. Peptide-3 is a dodecapeptide able to interact with MDM2 at the levels of the interaction region of the MDM4 and MDM2 proteins, thereby interfering with the coopeartivy function of the proteins in the regulation of p53. This peptide is indeed able to specifically activate p53 and to cause apoptotis in different cancer cell lines and tumor growth inhibition in xenograft models. Three different experimental conditions have been analysed compared to untreated cells at time 0 (NT cells, the starting point of the treatment): cells treated with DMSO solvent (DMSO); treated with peptide-3 (Pep3) and with control peptide (Pep3M). The analysis has been performed at 24 and 48 hours after treatment. In addition, untreated cells after 24 hours of growth have been analysed as further control. All analyses have been performed in triplicates.
2017-04-18 | E-GEOD-62855 | biostudies-arrayexpress
Project description:CDK4 inhibition diminishes p53 activation by Mdm2-antagonists
| PRJNA450932 | ENA
Project description:KT-253 is a potent and selective heterobifunctional MDM2 degrader with superior activity to MDM2/p53 small molecule inhibitors. RS4;11 cells treated with KT-253 indicated no off-target protein degradation. All significantly upregulated proteins are p53 and its target genes. KT-253 overcomes p53/MDM2 feedback loop. Targeted proteomics analysis of MDM2 levels in RS4;11 cells shows that KT-253 (150 nM KT-253 for 15 minutes) can achieve greater than 90% degradation of MDM2 within 1 hour posttreatment, whereas MDM2 levels continued to increase 1 hour after treatment with DS-3032 A single dose of KT-253 drives sustained tumor regression in ALL xenografts. Targeted proteomic analysis of tumors demonstrates robust degradation of MDM2 1-hour post dosing with KT-253. This is associated with activation of the p53 pathway as evidenced by a corresponding upregulation of proteomics biomarkers p53, p21, and PHLDA3.
2025-05-07 | PXD057859 | Pride
Project description:Proctor2008 - p53/Mdm2 circuit - p53 stabilisation by p14ARF
This model is described in the article:
Explaining oscillations and
variability in the p53-Mdm2 system.
Proctor CJ, Gray DA.
BMC Syst Biol 2008; 2: 75
Abstract:
BACKGROUND: In individual living cells p53 has been found to
be expressed in a series of discrete pulses after DNA damage.
Its negative regulator Mdm2 also demonstrates oscillatory
behaviour. Attempts have been made recently to explain this
behaviour by mathematical models but these have not addressed
explicit molecular mechanisms. We describe two stochastic
mechanistic models of the p53/Mdm2 circuit and show that
sustained oscillations result directly from the key biological
features, without assuming complicated mathematical functions
or requiring more than one feedback loop. Each model examines a
different mechanism for providing a negative feedback loop
which results in p53 activation after DNA damage. The first
model (ARF model) looks at the mechanism of p14ARF which
sequesters Mdm2 and leads to stabilisation of p53. The second
model (ATM model) examines the mechanism of ATM activation
which leads to phosphorylation of both p53 and Mdm2 and
increased degradation of Mdm2, which again results in p53
stabilisation. The models can readily be modified as further
information becomes available, and linked to other models of
cellular ageing. RESULTS: The ARF model is robust to changes in
its parameters and predicts undamped oscillations after DNA
damage so long as the signal persists. It also predicts that if
there is a gradual accumulation of DNA damage, such as may
occur in ageing, oscillations break out once a threshold level
of damage is acquired. The ATM model requires an additional
step for p53 synthesis for sustained oscillations to develop.
The ATM model shows much more variability in the oscillatory
behaviour and this variability is observed over a wide range of
parameter values. This may account for the large variability
seen in the experimental data which so far has examined ARF
negative cells. CONCLUSION: The models predict more regular
oscillations if ARF is present and suggest the need for further
experiments in ARF positive cells to test these predictions.
Our work illustrates the importance of systems biology
approaches to understanding the complex role of p53 in both
ageing and cancer.
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2024-09-02 | BIOMD0000000189 | BioModels
Project description:We performed an shRNA-based RNAi interference screen targeting around 5,000 genes in eight Burkitt lymphoma cell lines. MDM4 and CDKN3 were essential genes in four p53 wild-type Burkitt lymphoma cell lines, but not in four p53 mutant cell lines. To investigate the effect of the gene knock-down on cellular pathways, we performed single knock-downs and studied the gene expression profile. p53 pathway was activated after knock down of MDM4 or its close homologue MDM2, while proliferation markers were downregulated.
2019-08-01 | E-MTAB-7134 | biostudies-arrayexpress
Project description:The MDM2 oncoprotein is an essential component of the p53 pathway. Although MDM2 has been widely described as a major negative regulator of the p53 tumor suppressor, growing evidences support the notion that Mdm2 functions are also mediated through p53 independent mechanisms. We found that MDM2 is recruited on chromatin. By ChIP-Seq (using MDM2 antibody) of H1299 cells exhibiting MDM2 recruitment on chromatin, we identified at the whole genome level MDM2 binding sites. Both input and IPped-DNA were exhaustively sequenced and mapped on human genome
2016-06-09 | GSE64439 | GEO