CDK Inhibitors: Positive and Negative Regulators of G1-Phase Progression
Total Page:16
File Type:pdf, Size:1020Kb
Load more
Recommended publications
-
Selective Targeting of Cyclin E1-Amplified High-Grade Serous Ovarian Cancer by Cyclin-Dependent Kinase 2 and AKT Inhibition
Published OnlineFirst September 23, 2016; DOI: 10.1158/1078-0432.CCR-16-0620 Biology of Human Tumors Clinical Cancer Research Selective Targeting of Cyclin E1-Amplified High-Grade Serous Ovarian Cancer by Cyclin- Dependent Kinase 2 and AKT Inhibition George Au-Yeung1,2, Franziska Lang1, Walid J. Azar1, Chris Mitchell1, Kate E. Jarman3, Kurt Lackovic3,4, Diar Aziz5, Carleen Cullinane1,6, Richard B. Pearson1,2,7, Linda Mileshkin2,8, Danny Rischin2,8, Alison M. Karst9, Ronny Drapkin10, Dariush Etemadmoghadam1,2,5, and David D.L. Bowtell1,2,7,11 Abstract Purpose: Cyclin E1 (CCNE1) amplification is associated with Results: We validate CDK2 as a therapeutic target by demon- primary treatment resistance and poor outcome in high-grade strating selective sensitivity to gene suppression. However, we found serous ovarian cancer (HGSC). Here, we explore approaches to that dinaciclib did not trigger amplicon-dependent sensitivity in a target CCNE1-amplified cancers and potential strategies to over- panel of HGSC cell lines. A high-throughput compound screen come resistance to targeted agents. identified synergistic combinations in CCNE1-amplified HGSC, Experimental Design: To examine dependency on CDK2 in including dinaciclib and AKT inhibitors. Analysis of genomic data CCNE1-amplified HGSC, we utilized siRNA and conditional from TCGA demonstrated coamplification of CCNE1 and AKT2. shRNA gene suppression, and chemical inhibition using dina- Overexpression of Cyclin E1 and AKT isoforms, in addition to ciclib, a small-molecule CDK2 inhibitor. High-throughput mutant TP53, imparted malignant characteristics in untransformed compound screening was used to identify selective synergistic fallopian tube secretory cells, the dominant site of origin of HGSC. -
Cyclin K Interacts with Β-Catenin to Induce Cyclin D1 Expression And
Theranostics 2020, Vol. 10, Issue 24 11144 Ivyspring International Publisher Theranostics 2020; 10(24): 11144-11158. doi: 10.7150/thno.42578 Research Paper Cyclin K interacts with β-catenin to induce Cyclin D1 expression and facilitates tumorigenesis and radioresistance in lung cancer Guojun Yao*, Jing Tang*, Xijie Yang, Ye Zhao, Rui Zhou, Rui Meng, Sheng Zhang, Xiaorong Dong, Tao Zhang, Kunyu Yang, Gang Wu and Shuangbing Xu Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China. *These authors contributed equally to this work. Corresponding author: Shuangbing Xu or Gang Wu, Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China. E-mail: [email protected] or [email protected]. © The author(s). This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/). See http://ivyspring.com/terms for full terms and conditions. Received: 2019.11.29; Accepted: 2020.08.24; Published: 2020.09.11 Abstract Rationale: Radioresistance remains the major cause of local relapse and distant metastasis in lung cancer. However, the underlying molecular mechanisms remain poorly defined. This study aimed to investigate the role and regulatory mechanism of Cyclin K in lung cancer radioresistance. Methods: Expression levels of Cyclin K were measured by immunohistochemistry in human lung cancer tissues and adjacent normal lung tissues. Cell growth and proliferation, neutral comet and foci formation assays, G2/M checkpoint and a xenograft mouse model were used for functional analyses. Gene expression was examined by RNA sequencing and quantitative real-time PCR. -
Are Expressed by a Majority of Primary Human Acute Myeloid Leukemia Cells and Inducibility of the TLR Signaling Pathway Is Associated with a More Favorable Phenotype
Cancers 2019, 11 S1 of S19 Supplementary Material Functional Toll-Like Receptors (TLRs) are Expressed by a Majority of Primary Human Acute Myeloid Leukemia Cells and Inducibility of the TLR Signaling Pathway is Associated with a More Favorable Phenotype Annette K. Brenner and Øystein Bruserud Table S1. Median concentration increase in the secretion of 19 (16 patients with G-CSF, 67 patients with GM-CSF) soluble mediators as a result of targeting with four different TLR agonists. More than 5-fold increase is highlighted. LPS (TLR4) Flagellin (TLR5) R848 (TLR7/8) Pam3CSK4 (TLR1/2) IL-6 301.0 45.9 10.2 5.3 TNFα 188.7 10.6 5.0 1.5 IL-1β 89.7 9.2 1.1 1.5 CCL3 56.4 6.0 2.4 1.5 CCL2 52.6 9.4 4.3 2.8 G-CSF 51.9 2.7 1.0 1.0 CXCL1 38.0 5.8 1.4 1.5 CCL4 17.2 3.3 2.0 1.3 CCL5 14.5 2.1 1.3 1.1 MMP-1 11.1 3.4 1.4 1.1 CXCL5 8.3 4.3 1.3 1.4 CXCL8 6.0 4.3 1.7 1.3 GM-CSF 5.2 1.5 1.4 1.0 MMP-2 4.0 1.5 1.2 1.1 CXCL10 3.9 1.6 2.2 1.1 HGF 2.0 1.1 1.0 1.0 MMP-9 1.9 2.5 1.3 1.7 IL-1RA 1.8 1.3 1.3 1.0 Serpin E1 1.3 1.3 1.1 1.1 Cystatin C 1.1 1.1 1.0 1.0 Cancers 2019, 11 S2 of S19 Table S2. -
Constitutive Activation of Akt/Protein Kinase B in Melanoma Leads to Up- Regulation of Nuclear Factor-B and Tumor Progression1
[CANCER RESEARCH 62, 7335–7342, December 15, 2002] Constitutive Activation of Akt/Protein Kinase B in Melanoma Leads to Up- Regulation of Nuclear Factor-B and Tumor Progression1 Punita Dhawan, Amar B. Singh, Darrel L. Ellis, and Ann Richmond2 Departments of Veterans Affairs [A. R.], Cancer Biology [P. D., A. R.], Nephrology [A. B. S.], and Medicine, Division of Dermatology [D. L. E.], Vanderbilt University School of Medicine, Nashville, Tennessee 37232 ABSTRACT iting a cumulative melanoma risk of 1.9% compared with 0.04% of patients without dysplastic nevi (7). The current lifetime incidence The serine/threonine kinase Akt/protein kinase B and the pleiotropic of melanoma in the United States is estimated at 1:74 (8). The high transcription factor nuclear factor-B [NF-B (p50/p65)] play important incidence of dysplastic nevi and melanoma presents a large public roles in the control of cell proliferation, apoptosis, and oncogenesis. Pre- vious studies from our laboratory have shown the constitutive activation health problem. of NF-B in melanoma cells. However, the mechanism of this activation is Whereas histopathology is the current gold standard for the diag- not clearly understood. The purpose of this study was to explore the role nosis of atypical melanocytic lesions, interobserver correlation in the of Akt in the activation of NF-B during melanoma tumor progression. diagnosis of dysplastic nevi is variable (9, 10). The malignant poten- Based on our observation that two of the five melanoma cell lines exam- tial of dysplastic nevi and early melanomas is difficult to predict with ined exhibit constitutive Akt activation, we evaluated Akt activation by standard histological staining. -
Cytotoxic Effects and Changes in Gene Expression Profile
Toxicology in Vitro 34 (2016) 309–320 Contents lists available at ScienceDirect Toxicology in Vitro journal homepage: www.elsevier.com/locate/toxinvit Fusarium mycotoxin enniatin B: Cytotoxic effects and changes in gene expression profile Martina Jonsson a,⁎,MarikaJestoib, Minna Anthoni a, Annikki Welling a, Iida Loivamaa a, Ville Hallikainen c, Matti Kankainen d, Erik Lysøe e, Pertti Koivisto a, Kimmo Peltonen a,f a Chemistry and Toxicology Research Unit, Finnish Food Safety Authority (Evira), Mustialankatu 3, FI-00790 Helsinki, Finland b Product Safety Unit, Finnish Food Safety Authority (Evira), Mustialankatu 3, FI-00790 Helsinki, c The Finnish Forest Research Institute, Rovaniemi Unit, P.O. Box 16, FI-96301 Rovaniemi, Finland d Institute for Molecular Medicine Finland (FIMM), University of Helsinki, P.O. Box 20, FI-00014, Finland e Plant Health and Biotechnology, Norwegian Institute of Bioeconomy, Høyskoleveien 7, NO -1430 Ås, Norway f Finnish Safety and Chemicals Agency (Tukes), Opastinsilta 12 B, FI-00521 Helsinki, Finland article info abstract Article history: The mycotoxin enniatin B, a cyclic hexadepsipeptide produced by the plant pathogen Fusarium,isprevalentin Received 3 December 2015 grains and grain-based products in different geographical areas. Although enniatins have not been associated Received in revised form 5 April 2016 with toxic outbreaks, they have caused toxicity in vitro in several cell lines. In this study, the cytotoxic effects Accepted 28 April 2016 of enniatin B were assessed in relation to cellular energy metabolism, cell proliferation, and the induction of ap- Available online 6 May 2016 optosis in Balb 3T3 and HepG2 cells. The mechanism of toxicity was examined by means of whole genome ex- fi Keywords: pression pro ling of exposed rat primary hepatocytes. -
Mitosis Vs. Meiosis
Mitosis vs. Meiosis In order for organisms to continue growing and/or replace cells that are dead or beyond repair, cells must replicate, or make identical copies of themselves. In order to do this and maintain the proper number of chromosomes, the cells of eukaryotes must undergo mitosis to divide up their DNA. The dividing of the DNA ensures that both the “old” cell (parent cell) and the “new” cells (daughter cells) have the same genetic makeup and both will be diploid, or containing the same number of chromosomes as the parent cell. For reproduction of an organism to occur, the original parent cell will undergo Meiosis to create 4 new daughter cells with a slightly different genetic makeup in order to ensure genetic diversity when fertilization occurs. The four daughter cells will be haploid, or containing half the number of chromosomes as the parent cell. The difference between the two processes is that mitosis occurs in non-reproductive cells, or somatic cells, and meiosis occurs in the cells that participate in sexual reproduction, or germ cells. The Somatic Cell Cycle (Mitosis) The somatic cell cycle consists of 3 phases: interphase, m phase, and cytokinesis. 1. Interphase: Interphase is considered the non-dividing phase of the cell cycle. It is not a part of the actual process of mitosis, but it readies the cell for mitosis. It is made up of 3 sub-phases: • G1 Phase: In G1, the cell is growing. In most organisms, the majority of the cell’s life span is spent in G1. • S Phase: In each human somatic cell, there are 23 pairs of chromosomes; one chromosome comes from the mother and one comes from the father. -
The CDK4/6 Inhibitor LY2835219 Has Potent Activity in Combination with Mtor Inhibitor in Head and Neck Squamous Cell Carcinoma
www.impactjournals.com/oncotarget/ Oncotarget, Vol. 7, No. 12 The CDK4/6 inhibitor LY2835219 has potent activity in combination with mTOR inhibitor in head and neck squamous cell carcinoma Bo Mi Ku1,*, Seong Yoon Yi3,*, Jiae Koh1, Yeon-Hee Bae1, Jong-Mu Sun2, Se-hoon Lee2, Jin Seok Ahn2, Keunchil Park2, Myung-Ju Ahn2 1 Samsung Biomedical Research Institute, Seoul, Korea 2 Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea 3 Division of Hematology-Oncology, Department of Internal Medicine, Inje University Ilsan Paik Hospital, Gyeonggi-do, Korea *These authors contributed equally to this work Correspondence to: Myung-Ju Ahn, e-mail: [email protected] Keywords: head and neck cancer, CDK4/6 inhibitor, mTOR, cell cycle, targeted therapy Received: September 15, 2015 Accepted: January 23, 2016 Published: February 21, 2016 ABSTRACT Deletion of CDKN2A (p16) or amplification ofCCND1 (cyclin D1) occurs commonly in head and neck squamous cell carcinoma (HNSCC) and induces sustained cyclin- dependent kinase (CDK) 4/6 activation. Here, we report the antiproliferative activity of LY2835219, a selective CDK4/6 inhibitor through inhibition of CDK4/6-dependent Ser780 phosphorylation in retinoblastoma (RB) and induction of cell cycle arrest in HNSCC cells. In addition, we demonstrated the antitumor effects of HNSCC xenografts to LY2835219 in vivo. Given the limited effect in HNSCC as a single-agent treatment with LY2835219, a combinational strategy is required to enhance antitumor activity. At the molecular level, we found that LY2835219 inhibited activation of AKT and ERK, but not mTOR. The combination of LY2835219 with mTOR inhibitor was found to be more effective than either drug alone in vitro and in vivo. -
Identification of Candidate Repurposable Drugs to Combat COVID-19 Using a Signature-Based Approach
www.nature.com/scientificreports OPEN Identifcation of candidate repurposable drugs to combat COVID‑19 using a signature‑based approach Sinead M. O’Donovan1,10, Ali Imami1,10, Hunter Eby1, Nicholas D. Henkel1, Justin Fortune Creeden1, Sophie Asah1, Xiaolu Zhang1, Xiaojun Wu1, Rawan Alnafsah1, R. Travis Taylor2, James Reigle3,4, Alexander Thorman6, Behrouz Shamsaei4, Jarek Meller4,5,6,7,8 & Robert E. McCullumsmith1,9* The COVID‑19 pandemic caused by the novel SARS‑CoV‑2 is more contagious than other coronaviruses and has higher rates of mortality than infuenza. Identifcation of efective therapeutics is a crucial tool to treat those infected with SARS‑CoV‑2 and limit the spread of this novel disease globally. We deployed a bioinformatics workfow to identify candidate drugs for the treatment of COVID‑19. Using an “omics” repository, the Library of Integrated Network‑Based Cellular Signatures (LINCS), we simultaneously probed transcriptomic signatures of putative COVID‑19 drugs and publicly available SARS‑CoV‑2 infected cell lines to identify novel therapeutics. We identifed a shortlist of 20 candidate drugs: 8 are already under trial for the treatment of COVID‑19, the remaining 12 have antiviral properties and 6 have antiviral efcacy against coronaviruses specifcally, in vitro. All candidate drugs are either FDA approved or are under investigation. Our candidate drug fndings are discordant with (i.e., reverse) SARS‑CoV‑2 transcriptome signatures generated in vitro, and a subset are also identifed in transcriptome signatures generated from COVID‑19 patient samples, like the MEK inhibitor selumetinib. Overall, our fndings provide additional support for drugs that are already being explored as therapeutic agents for the treatment of COVID‑19 and identify promising novel targets that are worthy of further investigation. -
A Novel CDK9 Inhibitor Increases the Efficacy of Venetoclax (ABT-199) in Multiple Models of Hematologic Malignancies
Leukemia (2020) 34:1646–1657 https://doi.org/10.1038/s41375-019-0652-0 ARTICLE Molecular targets for therapy A novel CDK9 inhibitor increases the efficacy of venetoclax (ABT-199) in multiple models of hematologic malignancies 1 1 2,3 4 1 5 6 Darren C. Phillips ● Sha Jin ● Gareth P. Gregory ● Qi Zhang ● John Xue ● Xiaoxian Zhao ● Jun Chen ● 1 1 1 1 1 1 Yunsong Tong ● Haichao Zhang ● Morey Smith ● Stephen K. Tahir ● Rick F. Clark ● Thomas D. Penning ● 2,7 3 5 1 4 2,7 Jennifer R. Devlin ● Jake Shortt ● Eric D. Hsi ● Daniel H. Albert ● Marina Konopleva ● Ricky W. Johnstone ● 8 1 Joel D. Leverson ● Andrew J. Souers Received: 27 November 2018 / Revised: 18 October 2019 / Accepted: 13 November 2019 / Published online: 11 December 2019 © The Author(s) 2019 Abstract MCL-1 is one of the most frequently amplified genes in cancer, facilitating tumor initiation and maintenance and enabling resistance to anti-tumorigenic agents including the BCL-2 selective inhibitor venetoclax. The expression of MCL-1 is maintained via P-TEFb-mediated transcription, where the kinase CDK9 is a critical component. Consequently, we developed a series of potent small-molecule inhibitors of CDK9, exemplified by the orally active A-1592668, with CDK selectivity profiles 1234567890();,: 1234567890();,: that are distinct from related molecules that have been extensively studied clinically. Short-term treatment with A-1592668 rapidly downregulates RNA pol-II (Ser 2) phosphorylation resulting in the loss of MCL-1 protein and apoptosis in MCL-1- dependent hematologic tumor cell lines. This cell death could be attenuated by either inhibiting caspases or overexpressing BCL-2 protein. -
Cyclacel's CYC065 CDK Inhibitor Demonstrates Synergy With
Cyclacel’s CYC065 CDK Inhibitor Demonstrates Synergy With Venetoclax By Dual Targeting Of Chronic Lymphocytic Leukemia April 17, 2018 Suppression of both BCl-2 and Mcl-1 anti-apoptotic proteins is a novel strategy in CLL BERKELEY HEIGHTS, N.J., April 17, 2018 (GLOBE NEWSWIRE) -- Cyclacel Pharmaceuticals, Inc. (NASDAQ:CYCC) (NASDAQ:CYCCP) ("Cyclacel" or the "Company"), a biopharmaceutical company developing oral therapies that target various phases of cell cycle control for the treatment of cancer and other serious disorders, today announced the presentation by investigators led by William Plunkett, PhD, Professor and Deputy Chair, Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, Texas, of preclinical data demonstrating strong synergy between Cyclacel’s CDK2/9 inhibitor, CYC065, and the Bcl-2 inhibitor, venetoclax (ABT-199, AbbVie) in chronic lymphocytic leukemia (CLL) samples obtained from patients. The data were presented at the American Association for Cancer Research (AACR) Annual Meeting being held April 14-18, 2018 in Chicago, Illinois. “The MD Anderson data show that the combination of CYC065 and venetoclax is strongly synergistic in primary CLL cells from patients, including those with 17p deletions. In addition, the combination was active in two CLL samples which were resistant to either agent alone. These findings support the hypothesis that dual targeting of the Mcl-1- and Bcl-2-dependent mechanisms could induce synergistic cell death by apoptosis,” said Spiro Rombotis, President and Chief Executive Officer of Cyclacel. “Last weekend during the same AACR conference, we reported that CYC065 durably suppresses Mcl-1, a member of the Bcl-2 family of survival proteins, in patients with advanced solid tumors1. -
Human Cyclin-Dependent Kinase 12 (CDK12), Kinase Domain a Target Enabling Package (TEP)
Human Cyclin-Dependent Kinase 12 (CDK12), Kinase Domain A Target Enabling Package (TEP) Gene ID / UniProt ID / EC CDK12, 51755 / Q9NYV4/ 2.7.11.22, 2.7.11.23 CCNK, 8812 / O75909/ - Target Nominator Gregg Morin (UBC, Canada), Nathanael Gray (Harvard) SGC Authors Sarah E. Dixon-Clarke, Jonathan M. Elkins, Nathanael S. Gray, and Alex N. Bullock Collaborating Authors S.-W. Grace Cheng1, Tinghu Zhang2, Nicholas Kwiatkowski3, Calla M. Olson2, Brian J. Abraham3, Ann K. Greifenberg4, Scott B. Ficarro2, Yanke Liang2, Nancy M. Hannett3, Theresa Manz5, Mingfeng Hao2, Bartlomiej Bartkowiak6, Arno L. Greenleaf6, Jarrod A. Marto2, Matthias Geyer4, Richard A. Young3, and Gregg B. Morin1 Target PI Alex Bullock (SGC Oxford) Therapeutic Area(s) Oncology Disease Relevance CDK12 loss sensitises cancer cells to DNA damage Date approved by TEP 17th June 2016 Evaluation Group Document version Version 3 Document version date April 2018 DOI https://doi.org/10.5281/zenodo.1219680 Affiliations 1. Canada's Michael Smith Genome Sciences Centre, BC Cancer Agency 2. Department of Cancer Biology, Dana-Farber Cancer Institute 3. Whitehead Institute for Biomedical Research 4. Department of Structural Immunology, Institute of Innate Immunity 5. Pharmaceutical and Medicinal Chemistry, Saarland University 6. Department of Biochemistry, Duke University Medical Center USEFUL LINKS (Please note that the inclusion of links to external sites should not be taken as an endorsement of that site by the SGC in any way) SUMMARY OF PROJECT Cyclin-dependent kinase 12 (CDK12) phosphorylates RNA Pol II C-terminal domain (CTD) to promote transcriptional elongation of large DNA damage response genes. CDK12 is frequently mutated or amplified in cancer and its loss sensitises cells to DNA damage. -
Supplementary Table 1. in Vitro Side Effect Profiling Study for LDN/OSU-0212320. Neurotransmitter Related Steroids
Supplementary Table 1. In vitro side effect profiling study for LDN/OSU-0212320. Percent Inhibition Receptor 10 µM Neurotransmitter Related Adenosine, Non-selective 7.29% Adrenergic, Alpha 1, Non-selective 24.98% Adrenergic, Alpha 2, Non-selective 27.18% Adrenergic, Beta, Non-selective -20.94% Dopamine Transporter 8.69% Dopamine, D1 (h) 8.48% Dopamine, D2s (h) 4.06% GABA A, Agonist Site -16.15% GABA A, BDZ, alpha 1 site 12.73% GABA-B 13.60% Glutamate, AMPA Site (Ionotropic) 12.06% Glutamate, Kainate Site (Ionotropic) -1.03% Glutamate, NMDA Agonist Site (Ionotropic) 0.12% Glutamate, NMDA, Glycine (Stry-insens Site) 9.84% (Ionotropic) Glycine, Strychnine-sensitive 0.99% Histamine, H1 -5.54% Histamine, H2 16.54% Histamine, H3 4.80% Melatonin, Non-selective -5.54% Muscarinic, M1 (hr) -1.88% Muscarinic, M2 (h) 0.82% Muscarinic, Non-selective, Central 29.04% Muscarinic, Non-selective, Peripheral 0.29% Nicotinic, Neuronal (-BnTx insensitive) 7.85% Norepinephrine Transporter 2.87% Opioid, Non-selective -0.09% Opioid, Orphanin, ORL1 (h) 11.55% Serotonin Transporter -3.02% Serotonin, Non-selective 26.33% Sigma, Non-Selective 10.19% Steroids Estrogen 11.16% 1 Percent Inhibition Receptor 10 µM Testosterone (cytosolic) (h) 12.50% Ion Channels Calcium Channel, Type L (Dihydropyridine Site) 43.18% Calcium Channel, Type N 4.15% Potassium Channel, ATP-Sensitive -4.05% Potassium Channel, Ca2+ Act., VI 17.80% Potassium Channel, I(Kr) (hERG) (h) -6.44% Sodium, Site 2 -0.39% Second Messengers Nitric Oxide, NOS (Neuronal-Binding) -17.09% Prostaglandins Leukotriene,