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1.
Clin Transl Med ; 13(5): e1267, 2023 05.
Article in English | MEDLINE | ID: mdl-37226898

ABSTRACT

BACKGROUND: Renal medullary carcinoma (RMC) is a highly aggressive cancer in need of new therapeutic strategies. The neddylation pathway can protect cells from DNA damage induced by the platinum-based chemotherapy used in RMC. We investigated if neddylation inhibition with pevonedistat will synergistically enhance antitumour effects of platinum-based chemotherapy in RMC. METHODS: We evaluated the IC50 concentrations of the neddylation-activating enzyme inhibitor pevonedistat in vitro in RMC cell lines. Bliss synergy scores were calculated using growth inhibition assays following treatment with varying concentrations of pevonedistat and carboplatin. Protein expression was assessed by western blot and immunofluorescence assays. The efficacy of pevonedistat alone or in combination with platinum-based chemotherapy was evaluated in vivo in platinum-naïve and platinum-experienced patient-derived xenograft (PDX) models of RMC. RESULTS: The RMC cell lines demonstrated IC50 concentrations of pevonedistat below the maximum tolerated dose in humans. When combined with carboplatin, pevonedistat demonstrated a significant in vitro synergistic effect. Treatment with carboplatin alone increased nuclear ERCC1 levels used to repair the interstrand crosslinks induced by platinum salts. Conversely, the addition of pevonedistat to carboplatin led to p53 upregulation resulting in FANCD2 suppression and reduced nuclear ERCC1 levels. The addition of pevonedistat to platinum-based chemotherapy significantly inhibited tumour growth in both platinum-naïve and platinum-experienced PDX models of RMC (p < .01). CONCLUSIONS: Our results suggest that pevonedistat synergises with carboplatin to inhibit RMC cell and tumour growth through inhibition of DNA damage repair. These findings support the development of a clinical trial combining pevonedistat with platinum-based chemotherapy for RMC.


Subject(s)
Carcinoma, Medullary , Carcinoma, Renal Cell , Kidney Neoplasms , Humans , Carboplatin/pharmacology , Carboplatin/therapeutic use , Carcinoma, Renal Cell/drug therapy , Kidney Neoplasms/drug therapy
2.
Cancers (Basel) ; 13(23)2021 Nov 30.
Article in English | MEDLINE | ID: mdl-34885132

ABSTRACT

Renal medullary carcinoma (RMC) is a lethal malignancy affecting individuals with sickle hemoglobinopathies. Currently, no modifiable risk factors are known. We aimed to determine whether high-intensity exercise is a risk factor for RMC in individuals with sickle cell trait (SCT). We used multiple approaches to triangulate our conclusion. First, a case-control study was conducted at a single tertiary-care facility. Consecutive patients with RMC were compared to matched controls with similarly advanced genitourinary malignancies in a 1:2 ratio and compared on rates of physical activity and anthropometric measures, including skeletal muscle surface area. Next, we compared the rate of military service among our RMC patients to a similarly aged population of black individuals with SCT in the U.S. Further, we used genetically engineered mouse models of SCT to study the impact of exercise on renal medullary hypoxia. Compared with matched controls, patients with RMC reported higher physical activity and had higher skeletal muscle surface area. A higher proportion of patients with RMC reported military service than expected compared to the similarly-aged population of black individuals with SCT. When exposed to high-intensity exercise, mice with SCT demonstrated significantly higher renal medulla hypoxia compared to wild-type controls. These data suggest high-intensity exercise is the first modifiable risk factor for RMC in individuals with SCT.

3.
Sci Adv ; 7(14)2021 04.
Article in English | MEDLINE | ID: mdl-33811077

ABSTRACT

Epigenetic effectors "read" marks "written" on chromatin to regulate function and fidelity of the genome. Here, we show that this coordinated read-write activity of the epigenetic machinery extends to the cytoskeleton, with PBRM1 in the PBAF chromatin remodeling complex reading microtubule methyl marks written by the SETD2 histone methyltransferase. PBRM1 binds SETD2 methyl marks via BAH domains, recruiting PBAF components to the mitotic spindle. This read-write activity was required for normal mitosis: Loss of SETD2 methylation or pathogenic BAH domain mutations disrupt PBRM1 microtubule binding and PBAF recruitment and cause genomic instability. These data reveal PBRM1 functions beyond chromatin remodeling with domains that allow it to integrate chromatin and cytoskeletal activity via its acetyl-binding BD and methyl-binding BAH domains, respectively. Conserved coordinated activity of the epigenetic machinery on the cytoskeleton opens a previously unknown window into how chromatin remodeler defects can drive disease via both epigenetic and cytoskeletal dysfunction.


Subject(s)
Microtubules , Reading , Chromatin/metabolism , Chromatin Assembly and Disassembly , Cytoskeleton/metabolism , Microtubules/metabolism
4.
Cancer Cell ; 37(5): 720-734.e13, 2020 05 11.
Article in English | MEDLINE | ID: mdl-32359397

ABSTRACT

Renal medullary carcinoma (RMC) is a highly lethal malignancy that mainly afflicts young individuals of African descent and is resistant to all targeted agents used to treat other renal cell carcinomas. Comprehensive genomic and transcriptomic profiling of untreated primary RMC tissues was performed to elucidate the molecular landscape of these tumors. We found that RMC was characterized by high replication stress and an abundance of focal copy-number alterations associated with activation of the stimulator of the cyclic GMP-AMP synthase interferon genes (cGAS-STING) innate immune pathway. Replication stress conferred a therapeutic vulnerability to drugs targeting DNA-damage repair pathways. Elucidation of these previously unknown RMC hallmarks paves the way to new clinical trials for this rare but highly lethal malignancy.


Subject(s)
Biomarkers, Tumor/metabolism , Carcinoma, Medullary/pathology , Carcinoma, Renal Cell/pathology , Chromosome Aberrations , DNA Replication , Kidney Neoplasms/pathology , SMARCB1 Protein/metabolism , Adult , Animals , Apoptosis , Biomarkers, Tumor/genetics , Carcinoma, Medullary/genetics , Carcinoma, Medullary/immunology , Carcinoma, Renal Cell/genetics , Carcinoma, Renal Cell/immunology , Cell Proliferation , Cohort Studies , DNA Copy Number Variations , Female , Gene Expression Regulation, Neoplastic , Genomics , High-Throughput Nucleotide Sequencing , Humans , Kidney Neoplasms/genetics , Kidney Neoplasms/immunology , Male , Membrane Proteins/genetics , Membrane Proteins/metabolism , Mice , Mice, Nude , Nucleotidyltransferases/genetics , Nucleotidyltransferases/metabolism , Prognosis , Proto-Oncogene Proteins c-myc/genetics , Proto-Oncogene Proteins c-myc/metabolism , SMARCB1 Protein/genetics , Tumor Cells, Cultured , Xenograft Model Antitumor Assays
5.
Cancer Cell ; 35(2): 204-220.e9, 2019 02 11.
Article in English | MEDLINE | ID: mdl-30753823

ABSTRACT

Alterations in chromatin remodeling genes have been increasingly implicated in human oncogenesis. Specifically, the biallelic inactivation of the SWI/SNF subunit SMARCB1 results in the emergence of extremely aggressive pediatric malignancies. Here, we developed embryonic mosaic mouse models of malignant rhabdoid tumors (MRTs) that faithfully recapitulate the clinical-pathological features of the human disease. We demonstrated that SMARCB1-deficient malignancies exhibit dramatic activation of the unfolded protein response (UPR) and ER stress response via a genetically intact MYC-p19ARF-p53 axis. As a consequence, these tumors display an exquisite sensitivity to agents inducing proteotoxic stress and inhibition of the autophagic machinery. In conclusion, our findings provide a rationale for drug repositioning trials investigating combinations of agents targeting the UPR and autophagy in SMARCB1-deficient MRTs.


Subject(s)
Autophagy , Endoplasmic Reticulum Stress , Proteostasis , Rhabdoid Tumor/metabolism , SMARCB1 Protein/deficiency , Tumor Suppressor Protein p53/metabolism , Animals , Antineoplastic Agents/pharmacology , Autophagy/drug effects , Cell Line, Tumor , Cyclin-Dependent Kinase Inhibitor p16/genetics , Cyclin-Dependent Kinase Inhibitor p16/metabolism , Endoplasmic Reticulum Stress/drug effects , Female , Gene Expression Regulation, Neoplastic , Humans , Male , Mice, 129 Strain , Mice, Inbred C57BL , Mice, Knockout , Proteasome Inhibitors/pharmacology , Proteostasis/drug effects , Proto-Oncogene Proteins c-myc/genetics , Proto-Oncogene Proteins c-myc/metabolism , Rhabdoid Tumor/drug therapy , Rhabdoid Tumor/genetics , Rhabdoid Tumor/pathology , SMARCB1 Protein/genetics , Signal Transduction , Tumor Cells, Cultured , Tumor Suppressor Protein p53/deficiency , Tumor Suppressor Protein p53/genetics , Unfolded Protein Response
6.
Proc Natl Acad Sci U S A ; 110(32): E2950-7, 2013 Aug 06.
Article in English | MEDLINE | ID: mdl-23878245

ABSTRACT

Reactive intermediates such as reactive nitrogen species play essential roles in the cell as signaling molecules but, in excess, constitute a major source of cellular damage. We found that nitrosative stress induced by steady-state nitric oxide (NO) caused rapid activation of an ATM damage-response pathway leading to downstream signaling by this stress kinase to LKB1 and AMPK kinases, and activation of the TSC tumor suppressor. As a result, in an ATM-, LKB1-, TSC-dependent fashion, mTORC1 was repressed, as evidenced by decreased phosphorylation of S6K, 4E-BP1, and ULK1, direct targets of the mTORC1 kinase. Decreased ULK1 phosphorylation by mTORC1 at S757 and activation of AMPK to phosphorylate ULK1 at S317 in response to nitrosative stress resulted in increased autophagy: the LC3-II/LC3-I ratio increased as did GFP-LC3 puncta and acidic vesicles; p62 levels decreased in a lysosome-dependent manner, confirming an NO-induced increase in autophagic flux. Induction of autophagy by NO correlated with loss of cell viability, suggesting that, in this setting, autophagy was functioning primarily as a cytotoxic response to excess nitrosative stress. These data identify a nitrosative-stress signaling pathway that engages ATM and the LKB1 and TSC2 tumor suppressors to repress mTORC1 and regulate autophagy. As cancer cells are particularly sensitive to nitrosative stress, these data open another path for therapies capitalizing on the ability of reactive nitrogen species to induce autophagy-mediated cell death.


Subject(s)
AMP-Activated Protein Kinases/metabolism , Autophagy/physiology , Cell Cycle Proteins/metabolism , DNA-Binding Proteins/metabolism , Protein Serine-Threonine Kinases/metabolism , Reactive Oxygen Species/metabolism , TOR Serine-Threonine Kinases/metabolism , Tumor Suppressor Proteins/metabolism , AMP-Activated Protein Kinase Kinases , Animals , Ataxia Telangiectasia Mutated Proteins , Autophagy/drug effects , Blotting, Western , Cell Cycle Proteins/genetics , Cells, Cultured , DNA-Binding Proteins/genetics , Embryo, Mammalian/cytology , Fibroblasts/cytology , Fibroblasts/drug effects , Fibroblasts/metabolism , HeLa Cells , Humans , MCF-7 Cells , Mice , Mice, Knockout , Models, Biological , Multiprotein Complexes/metabolism , Nitric Oxide/metabolism , Nitric Oxide/physiology , Nitric Oxide Donors/metabolism , Nitric Oxide Donors/pharmacology , Phosphorylation/drug effects , Protein Serine-Threonine Kinases/genetics , Signal Transduction/drug effects , Spermine/analogs & derivatives , Spermine/metabolism , Spermine/pharmacology , Tuberous Sclerosis Complex 2 Protein , Tumor Suppressor Proteins/genetics
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