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1.
NAR Cancer ; 5(3): zcad039, 2023 Sep.
Article in English | MEDLINE | ID: mdl-37519629

ABSTRACT

CCNE1 amplification is a common alteration in high-grade serous ovarian cancer and occurs in 15-20% of these tumors. These amplifications are mutually exclusive with homologous recombination deficiency, and, as they have intact homologous recombination, are intrinsically resistant to poly (ADP-ribose) polymerase inhibitors or chemotherapy agents. Understanding the molecular mechanisms that lead to this mutual exclusivity may reveal therapeutic vulnerabilities that could be leveraged in the clinic in this still underserved patient population. Here, we demonstrate that CCNE1-amplified high-grade serous ovarian cancer cells rely on homologous recombination to repair collapsed replication forks. Cyclin-dependent kinase 2, the canonical partner of cyclin E1, uniquely regulates homologous recombination in this genetic context, and as such cyclin-dependent kinase 2 inhibition synergizes with DNA damaging agents in vitro and in vivo. We demonstrate that combining a selective cyclin-dependent kinase 2 inhibitor with a DNA damaging agent could be a powerful tool in the clinic for high-grade serous ovarian cancer.

2.
Cancer Res ; 79(13): 3479-3491, 2019 07 01.
Article in English | MEDLINE | ID: mdl-31064851

ABSTRACT

Recent studies suggest that targeting transcriptional machinery can lead to potent and selective anticancer effects in cancers dependent on high and constant expression of certain transcription factors for growth and survival. Cyclin-dependent kinase 7 (CDK7) is the catalytic subunit of the CDK-activating kinase complex. Its function is required for both cell-cycle regulation and transcriptional control of gene expression. CDK7 has recently emerged as an attractive cancer target because its inhibition leads to decreased transcript levels of oncogenic transcription factors, especially those associated with super-enhancers. Here, we describe a selective CDK7 inhibitor SY-1365, which is currently in clinical trials in populations of patients with ovarian and breast cancer (NCT03134638). In vitro, SY-1365 inhibited cell growth of many different cancer types at nanomolar concentrations. SY-1365 treatment decreased MCL1 protein levels, and cancer cells with low BCL2L1 (BCL-XL) expression were found to be more sensitive to SY-1365. Transcriptional changes in acute myeloid leukemia (AML) cell lines were distinct from those following treatment with other transcriptional inhibitors. SY-1365 demonstrated substantial antitumor effects in multiple AML xenograft models as a single agent; SY-1365-induced growth inhibition was enhanced in combination with the BCL2 inhibitor venetoclax. Antitumor activity was also observed in xenograft models of ovarian cancer, suggesting the potential for exploring SY-1365 in the clinic in both hematologic and solid tumors. Our findings support targeting CDK7 as a new approach for treating transcriptionally addicted cancers. SIGNIFICANCE: These findings demonstrate the molecular mechanism of action and potent antitumor activity of SY-1365, the first selective CDK7 inhibitor to enter clinical investigation.


Subject(s)
Apoptosis/drug effects , Cell Proliferation/drug effects , Cyclin-Dependent Kinases/antagonists & inhibitors , Ovarian Neoplasms/pathology , Protein Kinase Inhibitors/pharmacology , Animals , Cell Cycle/drug effects , Cyclin-Dependent Kinases/genetics , Cyclin-Dependent Kinases/metabolism , Female , High-Throughput Screening Assays , Humans , Mice , Mice, Inbred NOD , Mice, SCID , Models, Molecular , Ovarian Neoplasms/drug therapy , Ovarian Neoplasms/enzymology , Protein Kinase Inhibitors/chemistry , Tumor Cells, Cultured , Xenograft Model Antitumor Assays , Cyclin-Dependent Kinase-Activating Kinase
3.
Cancer Cell ; 31(4): 576-590.e8, 2017 04 10.
Article in English | MEDLINE | ID: mdl-28399412

ABSTRACT

Cyclins and cyclin-dependent kinases (CDKs) are hyperactivated in numerous human tumors. To identify means of interfering with cyclins/CDKs, we performed nine genome-wide screens for human microRNAs (miRNAs) directly regulating cell-cycle proteins. We uncovered a distinct class of miRNAs that target nearly all cyclins/CDKs, which are very effective in inhibiting cancer cell proliferation. By profiling the response of over 120 human cancer cell lines, we derived an expression-based algorithm that can predict the response of tumors to cell-cycle-targeting miRNAs. Using systemic administration of nanoparticle-formulated miRNAs, we inhibited tumor progression in seven mouse xenograft models, including three treatment-refractory patient-derived tumors, without affecting normal tissues. Our results highlight the utility of using cell-cycle-targeting miRNAs for treatment of refractory cancer types.


Subject(s)
Cell Cycle/genetics , Gene Expression Regulation, Neoplastic , MicroRNAs/genetics , 3' Untranslated Regions , Algorithms , Animals , Antineoplastic Agents/pharmacology , Breast Neoplasms/drug therapy , Breast Neoplasms/genetics , Cell Line, Tumor , Drug Delivery Systems/methods , Female , Genome-Wide Association Study , Humans , Mice, Inbred Strains , MicroRNAs/administration & dosage , MicroRNAs/pharmacology , Mutation , Nanoparticles , Proto-Oncogene Proteins p21(ras)/genetics , Xenograft Model Antitumor Assays
4.
Dev Cell ; 30(3): 255-67, 2014 Aug 11.
Article in English | MEDLINE | ID: mdl-25087893

ABSTRACT

D-type cyclins (D1, D2, and D3) are components of the mammalian core cell-cycle machinery and function to drive cell proliferation. Here, we report that D-cyclins perform a rate-limiting antiapoptotic function in vivo. We found that acute shutdown of all three D-cyclins in bone marrow of adult mice resulted in massive apoptosis of all hematopoietic cell types. We demonstrate that adult hematopoietic stem cells are particularly dependent on D-cyclins for survival and that they are especially sensitive to cyclin D loss. Surprisingly, we found that the antiapoptotic function of D-cyclins also operates in quiescent hematopoietic stem and progenitor cells. Our analyses revealed that D-cyclins repress the expression of the death receptor Fas and its ligand, FasL. Acute ablation of D-cyclins upregulated these proapoptotic genes and led to Fas- and caspase 8-dependent apoptosis. These results reveal an unexpected function of cell-cycle proteins in controlling apoptosis in normal cell homeostasis.


Subject(s)
Apoptosis/genetics , Cyclins/metabolism , Fas Ligand Protein/metabolism , Hematopoietic Stem Cells/cytology , fas Receptor/metabolism , Animals , Caspase 8/metabolism , Cell Cycle/genetics , Cell Proliferation , Cyclin D1/genetics , Cyclins/genetics , Fas Ligand Protein/genetics , Hematopoietic Stem Cells/metabolism , Ligands , Mice , Mice, Knockout , fas Receptor/genetics
5.
Nature ; 510(7506): 547-51, 2014 Jun 26.
Article in English | MEDLINE | ID: mdl-24870244

ABSTRACT

Insulin constitutes a principal evolutionarily conserved hormonal axis for maintaining glucose homeostasis; dysregulation of this axis causes diabetes. PGC-1α (peroxisome-proliferator-activated receptor-γ coactivator-1α) links insulin signalling to the expression of glucose and lipid metabolic genes. The histone acetyltransferase GCN5 (general control non-repressed protein 5) acetylates PGC-1α and suppresses its transcriptional activity, whereas sirtuin 1 deacetylates and activates PGC-1α. Although insulin is a mitogenic signal in proliferative cells, whether components of the cell cycle machinery contribute to its metabolic action is poorly understood. Here we report that in mice insulin activates cyclin D1-cyclin-dependent kinase 4 (Cdk4), which, in turn, increases GCN5 acetyltransferase activity and suppresses hepatic glucose production independently of cell cycle progression. Through a cell-based high-throughput chemical screen, we identify a Cdk4 inhibitor that potently decreases PGC-1α acetylation. Insulin/GSK-3ß (glycogen synthase kinase 3-beta) signalling induces cyclin D1 protein stability by sequestering cyclin D1 in the nucleus. In parallel, dietary amino acids increase hepatic cyclin D1 messenger RNA transcripts. Activated cyclin D1-Cdk4 kinase phosphorylates and activates GCN5, which then acetylates and inhibits PGC-1α activity on gluconeogenic genes. Loss of hepatic cyclin D1 results in increased gluconeogenesis and hyperglycaemia. In diabetic models, cyclin D1-Cdk4 is chronically elevated and refractory to fasting/feeding transitions; nevertheless further activation of this kinase normalizes glycaemia. Our findings show that insulin uses components of the cell cycle machinery in post-mitotic cells to control glucose homeostasis independently of cell division.


Subject(s)
Cell Cycle , Cyclin D1/metabolism , Cyclin-Dependent Kinase 4/metabolism , Glucose/metabolism , Insulin/metabolism , Signal Transduction , Acetylation , Amino Acids/pharmacology , Animals , Cell Line, Tumor , Cell Nucleus/metabolism , Cells, Cultured , Cyclin D1/deficiency , Cyclin D1/genetics , Cyclin-Dependent Kinase 4/antagonists & inhibitors , Diabetes Mellitus/metabolism , Enzyme Activation , Fasting , Gene Deletion , Gluconeogenesis/genetics , Glycogen Synthase Kinase 3/metabolism , Glycogen Synthase Kinase 3 beta , Hepatocytes/cytology , Hepatocytes/drug effects , Hepatocytes/metabolism , Histone Acetyltransferases/metabolism , Homeostasis , Humans , Hyperglycemia/metabolism , Hyperinsulinism/metabolism , Male , Mice , Phosphorylation , RNA, Messenger/analysis , RNA, Messenger/genetics , Transcription Factors/metabolism , Transcription, Genetic/drug effects
7.
Cancer Cell ; 22(4): 438-51, 2012 Oct 16.
Article in English | MEDLINE | ID: mdl-23079655

ABSTRACT

D-cyclins represent components of cell cycle machinery. To test the efficacy of targeting D-cyclins in cancer treatment, we engineered mouse strains that allow acute and global ablation of individual D-cyclins in a living animal. Ubiquitous shutdown of cyclin D1 or inhibition of cyclin D-associated kinase activity in mice bearing ErbB2-driven mammary carcinomas triggered tumor cell senescence, without compromising the animals' health. Ablation of cyclin D3 in mice bearing Notch1-driven T cell acute lymphoblastic leukemias (T-ALL) triggered tumor cell apoptosis. Such selective killing of leukemic cells can also be achieved by inhibiting cyclin D associated kinase activity in mouse and human T-ALL models. Inhibition of cyclin D-kinase activity represents a highly-selective anticancer strategy that specifically targets cancer cells without significantly affecting normal tissues.


Subject(s)
Cyclin D/physiology , Neoplasms/etiology , Animals , Apoptosis , Cell Cycle Checkpoints , Cyclin D/antagonists & inhibitors , Cyclin-Dependent Kinase 4/antagonists & inhibitors , Female , Humans , Mammary Neoplasms, Experimental/etiology , Mice , Neoplasms/drug therapy , Neoplasms/pathology , Precursor T-Cell Lymphoblastic Leukemia-Lymphoma/drug therapy , Precursor T-Cell Lymphoblastic Leukemia-Lymphoma/etiology , Receptor, ErbB-2/analysis
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