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MDM2 inhibition enhances immune checkpoint inhibitor therapy in melanoma

ABSTRACT: Immune checkpoint therapy has improved outcome of patients with advanced melanoma, however the tumor becomes refractory in a large number of patients. Therefore, novel combination therapies that enhance anti-melanoma immunity are highly desirable. We studied the impact of MDM2 (mouse double minute 2) inhibition, leading to p53 activation, on response to anti-PD-1 immunotherapy in melanoma. MDM2 treatment caused upregulation of MHC II and IL-15 in melanoma cells in a p53 dependent manner. Survival of melanoma bearing mice improved upon combining anti-PD1 and MDM2 inhibition in vivo. Lack of IL-15Rα in T cells abrogated the beneficial effect of the combined treatment. This gene expression study was performed to determine potential effects of MDM2 inhibition on genes in the melanoma microenvironment.

ORGANISM(S): Mus musculus

PROVIDER: GSE184524 | GEO | 2024/08/22

REPOSITORIES: GEO

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CDK4 inhibition diminishes p53 activation by Mdm2-antagonists

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

MDM2 and MDM4 are Therapeutic Vulnerabilities in Malignant Rhabdoid Tumors

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

Genome-wide maps of chromatin binding site for Mdm2.

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

Targeting MDM2-induced p53 upregulation to enhance anti-leukemia immunity post allogeneic stem cell transplantation

Project description:Relapse after allo-HCT is a major cause of death of AML patients and results from immune evasion of AML blasts. Dysfunction of the p53 signaling pathway is frequent in AML and often caused by upregulation of the central p53 negative regulator Murine Double Minute 2 (MDM2). Besides its oncogenic effects p53 also regulates immune function and immune surveillance of solid cancer. We hypothesize that p53 also controls immune-related genes in AML cells and that p53 reactivation via MDM2-inhibition may enhance the immunogenicity of AML cells to allogeneic T cells.

2022-09-20 | GSE158103 | GEO

Pharmacological inhibition of WIP1 sensitizes acute myeloid leukemia cells to MDM2 inhibitor Nutlin-3a

Project description:The wild-type p53-inducible protein phosphatase WIP1, encoded by the PPM1D gene, is a negative regulator of p53 and is involved in cell cycle control and DNA damage stress-response. In acute myeloid leukemia (AML), the restoration of p53 activity through MDM2 inhibition proved efficacy in a number of combination strategies. We investigated the therapeutic potential of its inhibition through the selective WIP1 inhibitor (WIP1i) GSK2830371, in association with the MDM2 inhibitor Nutlin-3a (Nut-3a) in a panel of AML cell lines and performed gene expression analysis of single agent and combined treatments. A p53-related signature was significantly upregulated in the TP53-wildtype MV-4-11 AML cell line. Moreover, drug-specific transcriptional changes likely contribute to the synergistic combination effect.

2021-05-06 | GSE156182 | GEO

A circular RNA from the MDM2 locus regulates proliferation by suppressing basal p53 levels

Project description:Circular RNAs (circRNAs) are a class of noncoding RNAs produced by a non-canonical form of alternative splicing called back-splicing. To investigate a potential role of circRNAs in the p53 pathway, we analyzed RNA-seq data from colorectal cancer cell lines (HCT116, RKO and SW48) in the presence or absence of DNA damage. Surprisingly, unlike the strong p53-dependent induction of hundreds of p53-induced mRNAs, only a few circRNAs were induced from the p53-induced genes. Circ-MDM2, an annotated circRNA from the MDM2 locus, was one of the handful of circRNAs that originated from a p53-induced gene. Given the central role of MDM2 in suppressing p53 protein levels and p53 activity, we investigated the function of circ-MDM2. Knocking down circ-MDM2 with siRNAs that targeted the circ-MDM2 junction and had no effect on linear MDM2 mRNA, resulted in increased basal p53 levels and growth defects in vitro and in vivo. Consistent with these results, transcriptome profiling showed increased expression of several direct p53 targets, reduced Rb phosphorylation and defects in G1-S progression upon silencing circ-MDM2. Our results reveal the role of a novel circRNA by which the MDM2 locus suppresses p53 levels and cell cycle progression.

2020-03-04 | GSE138016 | GEO

Charting the impact of supraphysiologic MDM2 on gene regulatory circuits in sarcoma

Project description:Amplification of the ubiquitin ligase MDM2 is a common mechanism of P53 inactivation across human tumors. Here we investigated the impact of supraphysiologic MDM2 expression on chromatin topology, gene expression and cellular phenotypes in liposarcoma tumors and models. We identified three independent gene regulatory circuits that predominate in aggressive, dedifferentiated tumors. RUNX and AP-1 family transcription factors bind a shared set of enhancers associated with mesenchymal lineage genes that underlie the developmental state of these tumors. P53 and MDM2 co-occupy enhancers and promoters associated with P53 pathways. When highly expressed, MDM2 also binds an additional set of P53-independent promoters that engage in multi-way physical interactions and regulate genes involved in cell division, RNA splicing, translation and stress responses. We find that liposarcoma cells with low to moderate MDM2 levels are sensitive to P53 inhibitors and their combination with pro-apoptotic agents, but that cells with very high-level MDM2 amplification and expression resist treatment. Hence, heterogeneity of MDM2 expression between and within tumors may compromise therapeutic regimens. In conclusion, we distinguished P53-dependent and P53-independent circuits in MDM2 copy number amplified tumors whose interplay has implications for targeted therapy.

2023-04-10 | GSE213300 | GEO

Mdm2 enhances stemness-promoting chromatin modifications through the Polycomb Repressor Complex 2 in a p53-Independent Manner [RNA-Seq]

Project description:The Mdm2 oncoprotein ubiquitinates and antagonizes p53 but may also carry out p53-independent functions. Here we report that Mdm2 is required for the efficient generation of induced pluripotent stem cells (iPSCs) from murine embryonic fibroblasts, in the absence of p53. Similarly, Mdm2 depletion in the context of p53 deficiency also promoted the differentiation of human mesenchymal stem cells and diminished clonogenic survival of cancer cells. Most of the Mdm2-controlled genes also responded to the inactivation of the Polycomb Repressor Complex 2 (PRC2) and its catalytic component EZH2. Mdm2 physically associated with EZH2 on chromatin, enhancing the trimethylation of Histone 3 at lysine 27 and the ubiquitination of Histone 2A at lysine 119 (H2AK119) at its target genes. Removing Mdm2 simultaneously with the H2AK119 E3 ligase Ring1B/RNF2 further induced these genes and synthetically arrested cell proliferation. In conclusion, Mdm2 supports the Polycomb-mediated repression of lineage specific genes independent of p53. Expression profiling by high throughput sequencing of p53 ko MEFs, p53Mdm2 ko MEFs, p53ko Mdm2 C462A ki MEFs.

2015-12-31 | E-GEOD-73176 | biostudies-arrayexpress

Mdm2 enhances stemness-promoting chromatin modifications through the Polycomb Repressor Complex 2 in a p53-Independent Manner [HCT116 microarray]

2015-12-31 | E-GEOD-73294 | biostudies-arrayexpress

Cancer-associated MDM2 W329G mutant attenuates ribosomal stress-mediated p53 responses to promote cell survival and glycolysis

Project description:Although amplification/overexpression is the predominant mechanism for the oncogenic properties of MDM2, an increasing number of MDM2 somatic missense mutations were identified in cancer patients with the recent advances in sequencing technology. Here, we characterized an MDM2 cancer-associated mutant variant W329G identified from patient samples that contain a wild-type p53 gene. We found that the MDM2 W329G mutant was resistant to the inhibitory effect of ribosomal protein L11 (RPL11) on MDM2-mediated p53 ubiquitination and degradation, in line with its defect on RPL11 binding. Using isogenic U2OS cells with or without endogenous mdm2 W329G mutation, we demonstrated that the expression of classic p53 targets induced by ribosomal stress signals was reduced in mutant cells. RNA-seq analysis revealed that upon 5-FU treatment, the p53 response was significantly impaired. Also, the 5-FU-mediated repression of genes in cell cycle progression and DNA replication was diminished in W329G mutant-containing cells. Physiologically, U2OS W329G cells were more resistant to cell growth inhibition induced by ribosomal stress and exhibited higher glycolytic rates upon 5-FU treatment. Together, our data indicated that cancer-associated MDM2 W329G mutant attenuates ribosomal stress-mediated p53 responses to promote cell survival and glycolysis.

2024-05-13 | GSE267150 | GEO

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