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MDM2 antagonists overcome intrinsic resistance to CDK4/6 inhibition by inducing p21.
Vilgelm AE, Saleh N, Shattuck-Brandt R, Riemenschneider K, Slesur L, Chen SC, Johnson CA, Yang J, Blevins A, Yan C, Johnson DB, Al-Rohil RN, Halilovic E, Kauffmann RM, Kelley M, Ayers GD, Richmond A
(2019) Sci Transl Med 11:
MeSH Terms: Analysis of Variance, Animals, Blotting, Western, Cell Cycle, Cell Survival, Cyclin-Dependent Kinase 4, Cyclin-Dependent Kinase 6, Cyclin-Dependent Kinase Inhibitor p21, DNA Replication, Dimethyl Sulfoxide, Humans, Immunoprecipitation, MCF-7 Cells, Melanoma, Mice, Mice, Inbred BALB C, Mice, Inbred C57BL, Mice, Nude, Proteomics, Proto-Oncogene Proteins c-mdm2, Radioimmunoprecipitation Assay
Show Abstract · Added September 27, 2019
Intrinsic resistance of unknown mechanism impedes the clinical utility of inhibitors of cyclin-dependent kinases 4 and 6 (CDK4/6i) in malignancies other than breast cancer. Here, we used melanoma patient-derived xenografts (PDXs) to study the mechanisms for CDK4/6i resistance in preclinical settings. We observed that melanoma PDXs resistant to CDK4/6i frequently displayed activation of the phosphatidylinositol 3-kinase (PI3K)-AKT pathway, and inhibition of this pathway improved CDK4/6i response in a p21-dependent manner. We showed that a target of p21, CDK2, was necessary for proliferation in CDK4/6i-treated cells. Upon treatment with CDK4/6i, melanoma cells up-regulated cyclin D1, which sequestered p21 and another CDK inhibitor, p27, leaving a shortage of p21 and p27 available to bind and inhibit CDK2. Therefore, we tested whether induction of p21 in resistant melanoma cells would render them responsive to CDK4/6i. Because p21 is transcriptionally driven by p53, we coadministered CDK4/6i with a murine double minute (MDM2) antagonist to stabilize p53, allowing p21 accumulation. This resulted in improved antitumor activity in PDXs and in murine melanoma. Furthermore, coadministration of CDK4/6 and MDM2 antagonists with standard of care therapy caused tumor regression. Notably, the molecular features associated with response to CDK4/6 and MDM2 inhibitors in PDXs were recapitulated by an ex vivo organotypic slice culture assay, which could potentially be adopted in the clinic for patient stratification. Our findings provide a rationale for cotargeting CDK4/6 and MDM2 in melanoma.
Copyright © 2019 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.
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21 MeSH Terms
The proto-oncogene function of Mdm2 in bone.
Olivos DJ, Perrien DS, Hooker A, Cheng YH, Fuchs RK, Hong JM, Bruzzaniti A, Chun K, Eischen CM, Kacena MA, Mayo LD
(2018) J Cell Biochem 119: 8830-8840
MeSH Terms: Analysis of Variance, Animals, Bone Density, Bone Remodeling, Calcification, Physiologic, Cancellous Bone, Cell Line, Tumor, Female, Humans, Male, Mice, Mice, Inbred C57BL, Mice, Inbred DBA, Osteoblasts, Osteoclasts, Osteogenesis, Osteosarcoma, Proto-Oncogene Proteins c-mdm2, Proto-Oncogenes
Show Abstract · Added April 1, 2019
Mouse double minute 2 (Mdm2) is a multifaceted oncoprotein that is highly regulated with distinct domains capable of cellular transformation. Loss of Mdm2 is embryonically lethal, making it difficult to study in a mouse model without additional genetic alterations. Global overexpression through increased Mdm2 gene copy number (Mdm2 ) results in the development of hematopoietic neoplasms and sarcomas in adult animals. In these mice, we found an increase in osteoblastogenesis, differentiation, and a high bone mass phenotype. Since it was difficult to discern the cell lineage that generated this phenotype, we generated osteoblast-specific Mdm2 overexpressing (Mdm2 ) mice in 2 different strains, C57BL/6 and DBA. These mice did not develop malignancies; however, these animals and the MG63 human osteosarcoma cell line with high levels of Mdm2 showed an increase in bone mineralization. Importantly, overexpression of Mdm2 corrected age-related bone loss in mice, providing a role for the proto-oncogenic activity of Mdm2 in bone health of adult animals.
© 2018 Wiley Periodicals, Inc.
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2 Members
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19 MeSH Terms
MDM2 Antagonists Counteract Drug-Induced DNA Damage.
Vilgelm AE, Cobb P, Malikayil K, Flaherty D, Andrew Johnson C, Raman D, Saleh N, Higgins B, Vara BA, Johnston JN, Johnson DB, Kelley MC, Chen SC, Ayers GD, Richmond A
(2017) EBioMedicine 24: 43-55
MeSH Terms: Animals, Antineoplastic Combined Chemotherapy Protocols, Azepines, Cell Line, Tumor, Cyclin-Dependent Kinase Inhibitor p21, DNA Damage, DNA Replication, HCT116 Cells, Humans, Imidazoles, Melanoma, Mice, Piperazines, Protein Binding, Proto-Oncogene Proteins c-mdm2, Pyrimidines, Pyrrolidines, Tumor Suppressor Protein p53, Xenograft Model Antitumor Assays, para-Aminobenzoates
Show Abstract · Added June 20, 2018
Antagonists of MDM2-p53 interaction are emerging anti-cancer drugs utilized in clinical trials for malignancies that rarely mutate p53, including melanoma. We discovered that MDM2-p53 antagonists protect DNA from drug-induced damage in melanoma cells and patient-derived xenografts. Among the tested DNA damaging drugs were various inhibitors of Aurora and Polo-like mitotic kinases, as well as traditional chemotherapy. Mitotic kinase inhibition causes mitotic slippage, DNA re-replication, and polyploidy. Here we show that re-replication of the polyploid genome generates replicative stress which leads to DNA damage. MDM2-p53 antagonists relieve replicative stress via the p53-dependent activation of p21 which inhibits DNA replication. Loss of p21 promoted drug-induced DNA damage in melanoma cells and enhanced anti-tumor activity of therapy combining MDM2 antagonist with mitotic kinase inhibitor in mice. In summary, MDM2 antagonists may reduce DNA damaging effects of anti-cancer drugs if they are administered together, while targeting p21 can improve the efficacy of such combinations.
Copyright © 2017. Published by Elsevier B.V.
1 Communities
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MeSH Terms
Liposarcomatous differentiation in malignant phyllodes tumours is unassociated with MDM2 or CDK4 amplification.
Lyle PL, Bridge JA, Simpson JF, Cates JM, Sanders ME
(2016) Histopathology 68: 1040-5
MeSH Terms: Adult, Aged, Aged, 80 and over, Biomarkers, Tumor, Breast Neoplasms, Cell Differentiation, Cyclin-Dependent Kinase 4, Female, Gene Amplification, Humans, In Situ Hybridization, Fluorescence, Liposarcoma, Middle Aged, Nerve Sheath Neoplasms, Phenotype, Phyllodes Tumor, Proto-Oncogene Proteins c-mdm2
Show Abstract · Added February 15, 2016
AIMS - Breast sarcomas are rare, usually occurring in the setting of malignant phyllodes tumour (MPT). Heterologous differentiation commonly resembles well-differentiated or pleomorphic liposarcoma. In extramammary sites, these subtypes have different biological behaviours and distinct genetic alterations: MDM2 and CDK4 amplification in well-differentiated liposarcoma, and polyploidy with complex structural rearrangements in pleomorphic liposarcoma. The aim of this study was to investigate foci resembling well-differentiated liposarcoma in MPT for MDM2 and CDK4 amplification.
METHODS AND RESULTS - We evaluated the clinicopathological characteristics of MPTs received by the Vanderbilt Breast Consultation Service containing components resembling well-differentiated or pleomorphic liposarcoma. Cases with available tissue blocks were subjected to fluorescence in-situ hybridization with MDM2 and CDK4 probes. Thirty-eight MPTs with liposarcomatous components were available for review. The mean patient age was 49.8 years (range 26-84 years). In addition to well-differentiated liposarcoma, the following components were also present: high-grade undifferentiated sarcoma (n = 9; 23.7%), pleomorphic liposarcoma (n = 4; 10.5%), non-high-grade sarcoma not otherwise specified (n = 22; 57.9%), and malignant peripheral nerve sheath tumour-like (n = 2; 5.2%). Among 10 cases tested, none showed amplification of MDM2 or CDK4.
CONCLUSIONS - This study examined molecular changes in the well-differentiated liposarcomatous components of MPT. Despite histological similarity to well-differentiated liposarcoma of soft tissues, liposarcomatous differentiation in MPT lacks the molecular phenotype characteristic of extramammary well-differentiated liposarcoma.
© 2015 John Wiley & Sons Ltd.
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1 Members
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17 MeSH Terms
Pharmacologically Increasing Mdm2 Inhibits DNA Repair and Cooperates with Genotoxic Agents to Kill p53-Inactivated Ovarian Cancer Cells.
Carrillo AM, Hicks M, Khabele D, Eischen CM
(2015) Mol Cancer Res 13: 1197-205
MeSH Terms: Animals, Antineoplastic Combined Chemotherapy Protocols, Apoptosis, Cell Line, Tumor, Cell Proliferation, Cisplatin, Comet Assay, DNA Breaks, Double-Stranded, DNA Damage, DNA Repair, Etoposide, Female, Fibroblasts, HEK293 Cells, Humans, Imidazoles, Mice, Mice, Transgenic, Mutagens, Ovarian Neoplasms, Piperazines, Proto-Oncogene Proteins c-mdm2, Tumor Suppressor Protein p53
Show Abstract · Added February 22, 2016
UNLABELLED - The Mdm2 oncogene is a negative regulator of the p53 tumor suppressor and recently identified inhibitor of DNA break repair. Nutlin-3 is a small-molecule inhibitor of Mdm2-p53 interaction that can induce apoptosis in cancer cells through activation of p53. Although this is a promising therapy for those cancers with wild-type p53, half of all human cancers have inactivated p53. Here, we reveal that a previously unappreciated effect of Nutlin is inhibition of DNA break repair, stemming from its ability to increase Mdm2 protein levels. The Nutlin-induced increase in Mdm2 inhibited DNA double-strand break repair and prolonged DNA damage response signaling independent of p53. Mechanistically, this effect of Nutlin required Mdm2 and acted through Nbs1 of the Mre11-Rad50-Nbs1 DNA repair complex. In ovarian cancer cells, where >90% have inactivated p53, Nutlin combined with the genotoxic agents, cisplatin or etoposide, had a cooperative lethal effect resulting in increased DNA damage and apoptosis. Therefore, these data demonstrate an unexpected consequence of pharmacologically increasing Mdm2 levels that when used in combination with genotoxic agents induces synthetic lethality in ovarian cancer cells, and likely other malignant cell types, that have inactivated p53.
IMPLICATIONS - Data reveal a therapeutically beneficial effect of pharmacologically increasing Mdm2 levels combined with chemotherapeutic agents for malignancies that have lost functional p53.
©2015 American Association for Cancer Research.
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23 MeSH Terms
Helicobacter pylori bacteria alter the p53 stress response via ERK-HDM2 pathway.
Bhardwaj V, Noto JM, Wei J, Andl C, El-Rifai W, Peek RM, Zaika AI
(2015) Oncotarget 6: 1531-43
MeSH Terms: Animals, Cell Line, Tumor, Gerbillinae, Helicobacter Infections, Helicobacter pylori, Humans, MAP Kinase Signaling System, Proto-Oncogene Proteins c-mdm2, Stomach Neoplasms, Transfection, Tumor Suppressor Protein p53
Show Abstract · Added February 19, 2015
H. pylori infection is the strongest known risk factor for gastric cancer. Inhibition of host tumor suppressor mechanisms by the bacteria underlies the development of this disease. Among the tumor suppressors affected by H. pylori are p53 and E-cadherin, which inhibition has been shown to increase the risk of gastric cancer. In this report, we investigated the interaction between E-cadherin and p53 in H. pylori-infected cells. We found that downregulation of E-cadherin leads to cellular stress and activation of p53. In the setting of H. pylori infection, this mechanism, however, is disrupted. We found that although co-culture of gastric epithelial cells with H. pylori led to downregulation of E-cadherin and cellular stress, it resulted in inhibition of p53, which is mediated by intracellular Erk kinases and HDM2 protein induced by H. pylori. Experimental inhibition of HDM2/p53 interactions restored p53 activity, and decreased survival of infected cells. Collectively, our results revealed that regulation of p53 and E-cadherin is tightly linked through the p53 stress response mechanism that is inhibited by H. pylori via activation of Erk1/2-HDM2-p53 pathway leading to survival of damaged cells. This might be advantageous to the bacteria but may increase the cancer risk.
0 Communities
5 Members
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11 MeSH Terms
Bacterial Pathogen Helicobacter pylori: A Bad AKTor Inhibits p53 Protein Activity [corrected].
Zaika AI
(2015) Dig Dis Sci 60: 822-3
MeSH Terms: Female, Gastric Mucosa, Helicobacter Infections, Humans, Male, Proto-Oncogene Proteins c-akt, Proto-Oncogene Proteins c-mdm2, Tumor Suppressor Protein p53
Added April 11, 2016
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8 MeSH Terms
Mdm2 and aurora kinase a inhibitors synergize to block melanoma growth by driving apoptosis and immune clearance of tumor cells.
Vilgelm AE, Pawlikowski JS, Liu Y, Hawkins OE, Davis TA, Smith J, Weller KP, Horton LW, McClain CM, Ayers GD, Turner DC, Essaka DC, Stewart CF, Sosman JA, Kelley MC, Ecsedy JA, Johnston JN, Richmond A
(2015) Cancer Res 75: 181-93
MeSH Terms: Animals, Antineoplastic Combined Chemotherapy Protocols, Apoptosis, Aurora Kinase A, Azepines, Cell Proliferation, Humans, Imidazoles, Melanoma, Melanoma, Experimental, Mice, Inbred BALB C, Mice, Inbred C57BL, Mice, Nude, Piperazines, Protein Kinase Inhibitors, Proto-Oncogene Proteins c-mdm2, Pyrimidines
Show Abstract · Added January 20, 2015
Therapeutics that induce cancer cell senescence can block cell proliferation and promote immune rejection. However, the risk of tumor relapse due to senescence escape may remain high due to the long lifespan of senescent cells that are not cleared. Here, we show how combining a senescence-inducing inhibitor of the mitotic kinase Aurora A (AURKA) with an MDM2 antagonist activates p53 in senescent tumors harboring wild-type 53. In the model studied, this effect is accompanied by proliferation arrest, mitochondrial depolarization, apoptosis, and immune clearance of cancer cells by antitumor leukocytes in a manner reliant upon Ccl5, Ccl1, and Cxcl9. The AURKA/MDM2 combination therapy shows adequate bioavailability and low toxicity to the host. Moreover, the prominent response of patient-derived melanoma tumors to coadministered MDM2 and AURKA inhibitors offers a sound rationale for clinical evaluation. Taken together, our work provides a preclinical proof of concept for a combination treatment that leverages both senescence and immune surveillance to therapeutic ends.
©2014 American Association for Cancer Research.
2 Communities
4 Members
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17 MeSH Terms
Oncogenic protein MTBP interacts with MYC to promote tumorigenesis.
Grieb BC, Gramling MW, Arrate MP, Chen X, Beauparlant SL, Haines DS, Xiao H, Eischen CM
(2014) Cancer Res 74: 3591-602
MeSH Terms: 3T3 Cells, ATPases Associated with Diverse Cellular Activities, Animals, Apoptosis, Breast Neoplasms, Carrier Proteins, Cell Line, Tumor, Cell Proliferation, Cell Transformation, Neoplastic, DNA Helicases, Female, Gene Dosage, HEK293 Cells, Humans, Mice, Mice, Nude, Protein Binding, Proto-Oncogene Proteins c-mdm2, Proto-Oncogene Proteins c-myc, Rats
Show Abstract · Added May 27, 2014
Despite its involvement in most human cancers, MYC continues to pose a challenge as a readily tractable therapeutic target. Here we identify the MYC transcriptional cofactors TIP48 and TIP49 and MYC as novel binding partners of Mdm2-binding protein (MTBP), a functionally undefined protein that we show is oncogenic and overexpressed in many human cancers. MTBP associated with MYC at promoters and increased MYC-mediated transcription, proliferation, neoplastic transformation, and tumor development. In breast cancer specimens, we determined overexpression of both MYC and MTBP was associated with a reduction in 10-year patient survival compared with MYC overexpression alone. MTBP was also frequently co-amplified with MYC in many human cancers. Mechanistic investigations implicated associations with TIP48/TIP49 as well as MYC in MTBP function in cellular transformation and the growth of human breast cancer cells. Taken together, our findings show MTBP functions with MYC to promote malignancy, identifying this protein as a novel general therapeutic target in human cancer.
©2014 American Association for Cancer Research.
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1 Members
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20 MeSH Terms
Mdmx promotes genomic instability independent of p53 and Mdm2.
Carrillo AM, Bouska A, Arrate MP, Eischen CM
(2015) Oncogene 34: 846-56
MeSH Terms: ATP-Binding Cassette Transporters, Animals, Cell Cycle Proteins, DNA Damage, DNA Repair, DNA Repair Enzymes, DNA-Binding Proteins, Genomic Instability, Humans, MRE11 Homologue Protein, Mice, Mice, Knockout, Neoplasms, Nuclear Proteins, Proto-Oncogene Proteins, Proto-Oncogene Proteins c-mdm2, Signal Transduction, Tumor Suppressor Protein p53
Show Abstract · Added March 17, 2014
The oncogene Mdmx is overexpressed in many human malignancies, and together with Mdm2, negatively regulates the p53 tumor suppressor. However, a p53-independent function of Mdmx that impacts genome stability has been described, but this function is not well understood. In the present study, we determined that of the 13 different cancer types evaluated, 6-90% of those that had elevated levels of Mdmx had concurrent inactivation (mutated or deleted) of p53. We show elevated levels of Mdmx-inhibited double-strand DNA break repair and induced chromosome and chromatid breaks independent of p53, leading to genome instability. Mdmx impaired early DNA damage-response signaling, such as phosphorylation of the serine/threonine-glutamine motif, mediated by the ATM kinase. Moreover, we identified Mdmx associated with Nbs1 of the Mre11-Rad50-Nbs1 (MRN) DNA repair complex, and this association increased upon DNA damage and was detected at chromatin. Elevated Mdmx levels also increased cellular transformation in a p53-independent manner. Unexpectedly, all Mdmx-mediated phenotypes also occurred in cells lacking Mdm2 and were independent of the Mdm2-binding domain (RING) of Mdmx. Therefore, Mdmx-mediated inhibition of the DNA damage response resulted in delayed DNA repair and increased genome instability and transformation independent of p53 and Mdm2. Our results reveal a novel p53- and Mdm2-independent oncogenic function of Mdmx that provides new insight into the many cancers that overexpress Mdmx.
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18 MeSH Terms