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Flores NG, Fernández‐Aroca DM, Garnés‐García C, Domínguez‐Calvo A, Jiménez‐Suárez J, Sabater S, Fernández‐Aroca P, Andrés I, Cimas FJ, de Cárcer G, Belandia B, Palmero I, Huertas P, Ruiz‐Hidalgo MJ, Sánchez‐Prieto R. The CDK12-BRCA1 signaling axis mediates dinaciclib-associated radiosensitivity through p53-mediated cellular senescence. Mol Oncol 2025; 19:1265-1280. [PMID: 39626031 PMCID: PMC11977655 DOI: 10.1002/1878-0261.13773] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2024] [Revised: 10/14/2024] [Accepted: 11/15/2024] [Indexed: 04/09/2025] Open
Abstract
Pan-cyclin-dependent-kinase (CDK) inhibitors are a new class of targeted therapies that can act on multiple CDKs, with dinaciclib being one of the most promising compounds. Although used as a monotherapy, an interesting approach could be to combine it with radiotherapy. Here, we show that dinaciclib increases radiosensitivity in some experimental models of lung and colon cancer (A549 or HCT 116) but not in others (H1299 or HT-29). Dinaciclib did not alter serine-protein kinase ATM signalling or cell cycle profiling after ionising-radiation exposure, which have been described for other CDK inhibitors. Interestingly, in terms of apoptosis, although the combination renders a clear increase, no potentiation of the ionising-radiation-induced apoptosis was observed. Mechanistically, inhibition of CDK12 by dinaciclib diminishes BRCA1 expression, which decreases homologous recombination (HR) and probably promotes the nonhomologous end joining repair process (NHEJ), which ultimately promotes the induction of ionising-radiation-associated cellular senescence in a TP53-dependent manner, explaining the lack of effect observed in some experimental models. In conclusion, our report proposes a molecular mechanism, based on the signalling axis CDK12-BRCA1, involved in this newly identified therapeutic effect of dinaciclib, although other players implicated in HR should not be discarded. In addition, our data provide a rationale for more selective and personalised chemo/radiotherapy treatment according to the genetic background of the tumour.
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Affiliation(s)
- Natalia García Flores
- Laboratorio de Oncología Molecular, Unidad de Medicina Molecular, Instituto de BiomedicinaUniversidad de Castilla‐La ManchaAlbaceteSpain
- Unidad de Biomedicina de la UCLM, Unidad asociada al CSICAlbaceteSpain
| | - Diego M. Fernández‐Aroca
- Laboratorio de Oncología Molecular, Unidad de Medicina Molecular, Instituto de BiomedicinaUniversidad de Castilla‐La ManchaAlbaceteSpain
- Unidad de Biomedicina de la UCLM, Unidad asociada al CSICAlbaceteSpain
- Centre for Genomics and Child Health, Blizard Institute, Faculty of Medicine and DentistryQueen Mary University of LondonUK
| | - Cristina Garnés‐García
- Laboratorio de Oncología Molecular, Unidad de Medicina Molecular, Instituto de BiomedicinaUniversidad de Castilla‐La ManchaAlbaceteSpain
- Unidad de Biomedicina de la UCLM, Unidad asociada al CSICAlbaceteSpain
- Translational Cancer Research Group, Chronic Diseases and Cancer, Area 3, Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS)MadridSpain
| | - Andrés Domínguez‐Calvo
- Facultad de BiologíaUniversidad de SevillaSpain
- Centro Andaluz de Biología Molecular y Medicina Regenerativa‐CABIMERUniversidad de Sevilla‐CSIC‐Universidad Pablo de OlavideSpain
| | - Jaime Jiménez‐Suárez
- Laboratorio de Oncología Molecular, Unidad de Medicina Molecular, Instituto de BiomedicinaUniversidad de Castilla‐La ManchaAlbaceteSpain
- Unidad de Biomedicina de la UCLM, Unidad asociada al CSICAlbaceteSpain
| | - Sebastià Sabater
- Servicio de Oncología RadioterápicaComplejo Hospitalario Universitario de AlbaceteSpain
| | - Pablo Fernández‐Aroca
- Laboratorio de Oncología Molecular, Unidad de Medicina Molecular, Instituto de BiomedicinaUniversidad de Castilla‐La ManchaAlbaceteSpain
- Unidad de Biomedicina de la UCLM, Unidad asociada al CSICAlbaceteSpain
- Translational Cancer Research Group, Chronic Diseases and Cancer, Area 3, Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS)MadridSpain
| | - Ignacio Andrés
- Servicio de Oncología RadioterápicaComplejo Hospitalario Universitario de AlbaceteSpain
| | - Francisco J. Cimas
- Laboratorio de Oncología Molecular, Unidad de Medicina Molecular, Instituto de BiomedicinaUniversidad de Castilla‐La ManchaAlbaceteSpain
- Unidad de Biomedicina de la UCLM, Unidad asociada al CSICAlbaceteSpain
- Translational Cancer Research Group, Chronic Diseases and Cancer, Area 3, Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS)MadridSpain
- Área de Bioquímica y Biología Molecular, Facultad de MedicinaUniversidad de Castilla‐La ManchaAlbaceteSpain
| | - Guillermo de Cárcer
- Unidad de Biomedicina de la UCLM, Unidad asociada al CSICAlbaceteSpain
- Translational Cancer Research Group, Chronic Diseases and Cancer, Area 3, Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS)MadridSpain
- Departamento de Biología del CáncerInstituto de Investigaciones Biomédicas Sols‐Morreale (CSIC‐UAM)MadridEspaña
- CSIC Conexión‐Cáncer HubMadridSpain
| | - Borja Belandia
- Unidad de Biomedicina de la UCLM, Unidad asociada al CSICAlbaceteSpain
- Translational Cancer Research Group, Chronic Diseases and Cancer, Area 3, Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS)MadridSpain
- Departamento de Biología del CáncerInstituto de Investigaciones Biomédicas Sols‐Morreale (CSIC‐UAM)MadridEspaña
- CSIC Conexión‐Cáncer HubMadridSpain
| | - Ignacio Palmero
- Laboratorio de Senescencia Celular y Supresión Tumoral, Departamento de Biología del CáncerInstituto de Investigaciones Biomédicas Sols‐Morreale (CSIC‐UAM)MadridSpain
| | - Pablo Huertas
- Facultad de BiologíaUniversidad de SevillaSpain
- Centro Andaluz de Biología Molecular y Medicina Regenerativa‐CABIMERUniversidad de Sevilla‐CSIC‐Universidad Pablo de OlavideSpain
| | - María José Ruiz‐Hidalgo
- Laboratorio de Oncología Molecular, Unidad de Medicina Molecular, Instituto de BiomedicinaUniversidad de Castilla‐La ManchaAlbaceteSpain
- Unidad de Biomedicina de la UCLM, Unidad asociada al CSICAlbaceteSpain
- Translational Cancer Research Group, Chronic Diseases and Cancer, Area 3, Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS)MadridSpain
- Área de Bioquímica y Biología Molecular, Facultad de MedicinaUniversidad de Castilla‐La ManchaAlbaceteSpain
| | - Ricardo Sánchez‐Prieto
- Laboratorio de Oncología Molecular, Unidad de Medicina Molecular, Instituto de BiomedicinaUniversidad de Castilla‐La ManchaAlbaceteSpain
- Unidad de Biomedicina de la UCLM, Unidad asociada al CSICAlbaceteSpain
- Translational Cancer Research Group, Chronic Diseases and Cancer, Area 3, Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS)MadridSpain
- Departamento de Biología del CáncerInstituto de Investigaciones Biomédicas Sols‐Morreale (CSIC‐UAM)MadridEspaña
- CSIC Conexión‐Cáncer HubMadridSpain
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Gao Y, Zhang Z, Huang X, You M, Du C, Li N, Hao Y, Wang K, Ding X, Yang F, Cheng SQ, Luo J, Chen R, Yang P. HBV-associated hepatocellular carcinomas inhibit antitumor CD8 + T cell via the long noncoding RNA HDAC2-AS2. Nat Commun 2025; 16:2055. [PMID: 40021665 PMCID: PMC11871238 DOI: 10.1038/s41467-025-57367-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2024] [Accepted: 02/19/2025] [Indexed: 03/03/2025] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the most common malignancies worldwide. Extracellular vesicles (EV) are critical mediators of intercellular communication within the tumor microenvironment, and cancer-cell-secreted EVs often facilitate cancer progression. Here we show that in HBV-associated HCC, tumor-cell-derived EVs contain a TGFβ-inducible long noncoding RNA, termed HDAC2-AS2. EVs enriched with HDAC2-AS2 facilitate cancer progression by suppressing cytotoxicity of intra-tumor CD8+ T cells. Mechanistically, in activated cytotoxic CD8+ T cells, translocation of the transcription factor cyclin-dependent kinase 9 (CDK9), to the cytoplasm is critical for functional integrity. HDAC2-AS2 targets and blocks cytosolic CDK9, and this results in exhaustion of PD-1+CD8+ T cells and suppression of IFN-γ+CD8+ T cell cytotoxicity. Notably, we demonstrate that low CDK9 and high HDAC2-AS2 expressions are associated with poor survival of HCC, which can be rescued by anti-PD-1 therapy. These findings emphasize the significance of tumor-derived EVs in suppressing antitumor CD8+ T cell immunity to promote tumorigenesis, and highlight extracellular HDAC2-AS2 as a promising biomarker and therapeutic target for HCC.
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Affiliation(s)
- Yanan Gao
- State Key Laboratory of Epigenetic Regulation and Intervention, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, 100101, Beijing, China
| | - Zhenxing Zhang
- State Key Laboratory of Epigenetic Regulation and Intervention, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, 100101, Beijing, China
| | - Xuetao Huang
- State Key Laboratory of Epigenetic Regulation and Intervention, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, 100101, Beijing, China
- University of Chinese Academy of Sciences, 100101, Beijing, China
| | - Maojun You
- State Key Laboratory of Epigenetic Regulation and Intervention, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, 100101, Beijing, China
| | - Chengzhi Du
- State Key Laboratory of Epigenetic Regulation and Intervention, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, 100101, Beijing, China
- University of Chinese Academy of Sciences, 100101, Beijing, China
| | - Nan Li
- Department of Hepatic Surgery VI, Eastern Hepatobiliary Surgery Hospital, Naval Medical University, Shanghai, China
| | - Yajing Hao
- State Key Laboratory of Epigenetic Regulation and Intervention, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, 100101, Beijing, China
| | - Kang Wang
- Department of Hepatic Surgery VI, Eastern Hepatobiliary Surgery Hospital, Naval Medical University, Shanghai, China
| | - Xiang Ding
- University of Chinese Academy of Sciences, 100101, Beijing, China
- Laboratory of Proteomics, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China
| | - Fuquan Yang
- University of Chinese Academy of Sciences, 100101, Beijing, China
- Laboratory of Proteomics, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China
| | - Shu-Qun Cheng
- Department of Hepatic Surgery VI, Eastern Hepatobiliary Surgery Hospital, Naval Medical University, Shanghai, China
| | - Jianjun Luo
- State Key Laboratory of Epigenetic Regulation and Intervention, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, 100101, Beijing, China.
- University of Chinese Academy of Sciences, 100101, Beijing, China.
| | - Runsheng Chen
- State Key Laboratory of Epigenetic Regulation and Intervention, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, 100101, Beijing, China.
- University of Chinese Academy of Sciences, 100101, Beijing, China.
| | - Pengyuan Yang
- State Key Laboratory of Epigenetic Regulation and Intervention, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, 100101, Beijing, China.
- University of Chinese Academy of Sciences, 100101, Beijing, China.
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Kalin S, Comert Onder F. Discovery of potential RSK1 inhibitors for cancer therapy using virtual screening, molecular docking, molecular dynamics simulation, and MM/GBSA calculations. J Biomol Struct Dyn 2025; 43:1424-1444. [PMID: 38084766 DOI: 10.1080/07391102.2023.2291830] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2023] [Accepted: 11/23/2023] [Indexed: 01/16/2025]
Abstract
The p90 ribosomal protein S6 Kinase (RSK) family belongs to Ser/Thr protein kinases that includes four isoform RSK1-4 in mammals. The ribosomal protein S6 Kinase 1 (RSK1) is also known as ribosomal protein S6 kinase alpha-1 (RPS6KA1) is a special protein due to their two catalytic regions that is associated with abundantly various cancers and it is proposed as a drug target. Several RSK1 isoform inhibitors have been reported but none of them are used in clinical studies. Thus, we aimed to perform ligand pharmacophore mapping with the known inhibitor and structure-based virtual screening studies to determine potential candidates against RSK1-terminal kinase domains CTKD and NTKD. The studied compounds from the databases (ApexBio, ChEMBL, ChemDiv). The molecular docking study was performed with the resulted candidates by using CDOCKER and Glide/SP methods. The four candidates with the highest docking scores were used for further 100-ns molecular dynamics (MD) simulations and Molecular Mechanics Generalised Born and Surface Area (MM/GBSA) calculations. The root mean square deviation (RMSD) for protein complexes were found between 2 Å and 4 Å. Solvent accessible surface area (SASA), radius of gyration (Rg), and polar surface area (PSA) values were calculated for compounds. The binding free energies were calculated between -72.22 kcal/mol and -82.44 kcal/mol. The interaction diagrams showed that hydrogen bond, alkyl, and π-alkyl interactions were observed with specific residues such as Leu144, Lys94, Asp142 for RSK1-NTKD, and Cys532, Cys556, Lys447, Asn540 for RSK1-CTKD. The identified compounds may be potential inhibitor candidates of RSK1 following the preclinical studies.Communicated by Ramaswamy H. Sarma.
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Affiliation(s)
- Sevil Kalin
- Department of Medical System Biology, School of Graduate Students, Çanakkale Onsekiz Mart University, Çanakkale, Türkiye
| | - Ferah Comert Onder
- Department of Medical Biology, Faculty of Medicine, Çanakkale Onsekiz Mart University, Çanakkale, Türkiye
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Gerosa R, De Sanctis R, Jacobs F, Benvenuti C, Gaudio M, Saltalamacchia G, Torrisi R, Masci G, Miggiano C, Agustoni F, Pedrazzoli P, Santoro A, Zambelli A. Cyclin-dependent kinase 2 (CDK2) inhibitors and others novel CDK inhibitors (CDKi) in breast cancer: clinical trials, current impact, and future directions. Crit Rev Oncol Hematol 2024; 196:104324. [PMID: 38462150 DOI: 10.1016/j.critrevonc.2024.104324] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2023] [Revised: 01/31/2024] [Accepted: 03/07/2024] [Indexed: 03/12/2024] Open
Abstract
Aberrant cyclin-dependent kinase 2 (CDK2) activation has been identified as a main resistance mechanism to CDK4/6 inhibition in hormone-receptor positive (HR+) breast cancer. Additionally, consistent preclinical evidence states its crucial role in MYC and CCNE1 overexpressed cancer survival, such as triple-negative breast cancers (TNBC), thus representing an appealing and relatively unexplored target treatment opportunity. Despite emerging initial results of novel CDK2 inhibitors (CDK2i) activity, a comprehensive outcomes collection is currently absent from the scientific literature. We aim to provide an overview of ongoing clinical trials involving CDK2i in the context of metastatic breast cancer (mBC), either as monotherapy or in combination with other agents. The review extends beyond CDK2i to encompass novel emerging CDK4 inhibitors, combined CDK2/4/6 inhibitors, and the well-known pan-CDK inhibitors including those specifically directed at CDK2. Delving into the results, we critically appraise the observed clinical efficacy and offer valuable insights into their potential impact and future applications.
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Affiliation(s)
- Riccardo Gerosa
- Humanitas University, Department of Biomedical Sciences, Humanitas University, Via Rita Levi Montalcini 4, Milan, Pieve Emanuele 20090, Italy; Humanitas Clinical and Research Center-IRCCS, Humanitas Cancer Center, Via Manzoni 56, Milan, Rozzano 20089, Italy
| | - Rita De Sanctis
- Humanitas University, Department of Biomedical Sciences, Humanitas University, Via Rita Levi Montalcini 4, Milan, Pieve Emanuele 20090, Italy; Humanitas Clinical and Research Center-IRCCS, Humanitas Cancer Center, Via Manzoni 56, Milan, Rozzano 20089, Italy.
| | - Flavia Jacobs
- Humanitas University, Department of Biomedical Sciences, Humanitas University, Via Rita Levi Montalcini 4, Milan, Pieve Emanuele 20090, Italy; Humanitas Clinical and Research Center-IRCCS, Humanitas Cancer Center, Via Manzoni 56, Milan, Rozzano 20089, Italy
| | - Chiara Benvenuti
- Humanitas University, Department of Biomedical Sciences, Humanitas University, Via Rita Levi Montalcini 4, Milan, Pieve Emanuele 20090, Italy; Humanitas Clinical and Research Center-IRCCS, Humanitas Cancer Center, Via Manzoni 56, Milan, Rozzano 20089, Italy
| | - Mariangela Gaudio
- Humanitas University, Department of Biomedical Sciences, Humanitas University, Via Rita Levi Montalcini 4, Milan, Pieve Emanuele 20090, Italy; Humanitas Clinical and Research Center-IRCCS, Humanitas Cancer Center, Via Manzoni 56, Milan, Rozzano 20089, Italy
| | - Giuseppe Saltalamacchia
- Humanitas University, Department of Biomedical Sciences, Humanitas University, Via Rita Levi Montalcini 4, Milan, Pieve Emanuele 20090, Italy
| | - Rosalba Torrisi
- Humanitas University, Department of Biomedical Sciences, Humanitas University, Via Rita Levi Montalcini 4, Milan, Pieve Emanuele 20090, Italy
| | - Giovanna Masci
- Humanitas University, Department of Biomedical Sciences, Humanitas University, Via Rita Levi Montalcini 4, Milan, Pieve Emanuele 20090, Italy
| | - Chiara Miggiano
- Humanitas University, Department of Biomedical Sciences, Humanitas University, Via Rita Levi Montalcini 4, Milan, Pieve Emanuele 20090, Italy; Humanitas Clinical and Research Center-IRCCS, Humanitas Cancer Center, Via Manzoni 56, Milan, Rozzano 20089, Italy
| | - Francesco Agustoni
- Department of Internal Medicine and Medical Therapy, University of Pavia, Pavia, Italy; Medical Oncology Unit, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy
| | - Paolo Pedrazzoli
- Department of Internal Medicine and Medical Therapy, University of Pavia, Pavia, Italy; Medical Oncology Unit, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy
| | - Armando Santoro
- Humanitas University, Department of Biomedical Sciences, Humanitas University, Via Rita Levi Montalcini 4, Milan, Pieve Emanuele 20090, Italy; Humanitas Clinical and Research Center-IRCCS, Humanitas Cancer Center, Via Manzoni 56, Milan, Rozzano 20089, Italy
| | - Alberto Zambelli
- Humanitas University, Department of Biomedical Sciences, Humanitas University, Via Rita Levi Montalcini 4, Milan, Pieve Emanuele 20090, Italy; Humanitas Clinical and Research Center-IRCCS, Humanitas Cancer Center, Via Manzoni 56, Milan, Rozzano 20089, Italy
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Masci D, Naro C, Puxeddu M, Urbani A, Sette C, La Regina G, Silvestri R. Recent Advances in Drug Discovery for Triple-Negative Breast Cancer Treatment. Molecules 2023; 28:7513. [PMID: 38005235 PMCID: PMC10672974 DOI: 10.3390/molecules28227513] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2023] [Revised: 11/02/2023] [Accepted: 11/06/2023] [Indexed: 11/26/2023] Open
Abstract
Triple-negative breast cancer (TNBC) is one of the most heterogeneous and aggressive breast cancer subtypes with a high risk of death on recurrence. To date, TNBC is very difficult to treat due to the lack of an effective targeted therapy. However, recent advances in the molecular characterization of TNBC are encouraging the development of novel drugs and therapeutic combinations for its therapeutic management. In the present review, we will provide an overview of the currently available standard therapies and new emerging therapeutic strategies against TNBC, highlighting the promises that newly developed small molecules, repositioned drugs, and combination therapies have of improving treatment efficacy against these tumors.
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Affiliation(s)
- Domiziana Masci
- Department of Basic Biotechnological Sciences, Intensivological and Perioperative Clinics, Catholic University of the Sacred Heart, Largo Francesco Vito 1, 00168 Rome, Italy; (D.M.); (A.U.)
| | - Chiara Naro
- Department of Neurosciences, Section of Human Anatomy, Catholic University of the Sacred Heart, Largo Francesco Vito 1, 00168 Rome, Italy; (C.N.); (C.S.)
- GSTeP-Organoids Research Core Facility, Fondazione Policlinico Universitario A. Gemelli, IRCCS, 00168 Rome, Italy
| | - Michela Puxeddu
- Laboratory Affiliated to Istituto Pasteur Italia—Fondazione Cenci Bolognetti, Department of Drug Chemistry and Technologies, Sapienza University of Rome, Piazzale Aldo Moro 5, 00185 Rome, Italy; (M.P.); (G.L.R.)
| | - Andrea Urbani
- Department of Basic Biotechnological Sciences, Intensivological and Perioperative Clinics, Catholic University of the Sacred Heart, Largo Francesco Vito 1, 00168 Rome, Italy; (D.M.); (A.U.)
| | - Claudio Sette
- Department of Neurosciences, Section of Human Anatomy, Catholic University of the Sacred Heart, Largo Francesco Vito 1, 00168 Rome, Italy; (C.N.); (C.S.)
- GSTeP-Organoids Research Core Facility, Fondazione Policlinico Universitario A. Gemelli, IRCCS, 00168 Rome, Italy
| | - Giuseppe La Regina
- Laboratory Affiliated to Istituto Pasteur Italia—Fondazione Cenci Bolognetti, Department of Drug Chemistry and Technologies, Sapienza University of Rome, Piazzale Aldo Moro 5, 00185 Rome, Italy; (M.P.); (G.L.R.)
| | - Romano Silvestri
- Laboratory Affiliated to Istituto Pasteur Italia—Fondazione Cenci Bolognetti, Department of Drug Chemistry and Technologies, Sapienza University of Rome, Piazzale Aldo Moro 5, 00185 Rome, Italy; (M.P.); (G.L.R.)
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Evaluation of CDK9 Inhibition by Dinaciclib in Combination with Apoptosis Modulating izTRAIL for the Treatment of Colorectal Cancer. Biomedicines 2023; 11:biomedicines11030928. [PMID: 36979907 PMCID: PMC10045754 DOI: 10.3390/biomedicines11030928] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2022] [Revised: 03/07/2023] [Accepted: 03/09/2023] [Indexed: 03/19/2023] Open
Abstract
Treatment options for colorectal cancer (CRC), especially in advanced stages are still insufficient. There, the discovery of Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) was a bright spot. However, most cancers show resistance toward apoptotic signals. Cyclin-dependent kinase 9 (CDK9) plays a crucial role in cell cycle progression in most tissues. We recently demonstrated the role of CDK9 in mediating TRAIL resistance. In this work, we investigated the role of CDK9 in colorectal cancer. Immunohistochemical analysis of CDK9 expression in cancer and normal tissues of CRC specimens was performed. The effect of selective CDK9 inhibition in combination with TRAIL on CRC cells was analyzed via cell viability, colony formation, and induction of apoptosis by flow cytometry. The mechanism of action was conducted via western blotting. We now have confirmed overexpression of CDK9 in cancer tissues, with low expression associated with poorer survival in a subset of CRC patients. In-vitro, CDK9 inhibition could strongly promote TRAIL-induced cell death in TRAIL-resistant CRC cells. Mechanistically, CDK9 inhibition induced apoptosis by downregulation of antiapoptotic proteins, myeloid leukemia cell differentiation protein 1 (Mcl-1) and FLICE-inhibitory protein (c-FLIP). Overall, we identified CDK9 as a prognostic marker and combined CDK9 inhibition and TRAIL as a novel and promising therapeutic approaches for colorectal cancer.
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Al-Qasem AJ, Alves CL, Ehmsen S, Tuttolomondo M, Terp MG, Johansen LE, Vever H, Hoeg LVA, Elias D, Bak M, Ditzel HJ. Co-targeting CDK2 and CDK4/6 overcomes resistance to aromatase and CDK4/6 inhibitors in ER+ breast cancer. NPJ Precis Oncol 2022; 6:68. [PMID: 36153348 PMCID: PMC9509389 DOI: 10.1038/s41698-022-00311-6] [Citation(s) in RCA: 37] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2021] [Accepted: 08/30/2022] [Indexed: 11/09/2022] Open
Abstract
AbstractResistance to aromatase inhibitor (AI) treatment and combined CDK4/6 inhibitor (CDK4/6i) and endocrine therapy (ET) are crucial clinical challenges in treating estrogen receptor-positive (ER+) breast cancer. Understanding the resistance mechanisms and identifying reliable predictive biomarkers and novel treatment combinations to overcome resistance are urgently needed. Herein, we show that upregulation of CDK6, p-CDK2, and/or cyclin E1 is associated with adaptation and resistance to AI-monotherapy and combined CDK4/6i and ET in ER+ advanced breast cancer. Importantly, co-targeting CDK2 and CDK4/6 with ET synergistically impairs cellular growth, induces cell cycle arrest and apoptosis, and delays progression in AI-resistant and combined CDK4/6i and fulvestrant-resistant cell models and in an AI-resistant autocrine breast tumor in a postmenopausal xenograft model. Analysis of CDK6, p-CDK2, and/or cyclin E1 expression as a combined biomarker in metastatic lesions of ER+ advanced breast cancer patients treated with AI-monotherapy or combined CDK4/6i and ET revealed a correlation between high biomarker expression and shorter progression-free survival (PFS), and the biomarker combination was an independent prognostic factor in both patients cohorts. Our study supports the clinical development of therapeutic strategies co-targeting ER, CDK4/6 and CDK2 following progression on AI-monotherapy or combined CDK4/6i and ET to improve survival of patients exhibiting high tumor levels of CDK6, p-CDK2, and/or cyclin E1.
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Saddozai UAK, Wang F, Khattak S, Akbar MU, Badar M, Khan NH, Zhang L, Zhu W, Xie L, Li Y, Ji X, Guo X. Define the Two Molecular Subtypes of Epithelioid Malignant Pleural Mesothelioma. Cells 2022; 11:cells11182924. [PMID: 36139498 PMCID: PMC9497219 DOI: 10.3390/cells11182924] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2022] [Revised: 08/25/2022] [Accepted: 09/08/2022] [Indexed: 11/20/2022] Open
Abstract
Malignant pleural mesothelioma (MPM) is a fatal disease of respiratory system. Despite the availability of invasive biomarkers with promising results, there are still significant diagnostic and therapeutic challenges in the treatment of MPM. One of three main mesothelioma cell types, epithelioid mesothelioma makes up approximately 70% of all mesothelioma cases. Different observational findings are under process, but the molecular heterogeneity and pathogenesis of epithelioid malignant pleural mesothelioma (eMPM) are still not well understood. Through molecular analysis, expression profiling data were used to determine the possibility and optimal number of eMPM molecular subtypes. Next, clinicopathological characteristics and different molecular pathways of each subtype were analyzed to prospect the clinical applications and advanced mechanisms of eMPM. In this study, we identified two distinct epithelioid malignant pleural mesothelioma subtypes with distinct gene expression patterns. Subtype I eMPMs were involved in steroid hormone biosynthesis, porphyrin and chlorophyll metabolism, and drug metabolism, while subtype II eMPMs were involved in rational metabolism, tyrosine metabolism, and chemical carcinogenesis pathways. Additionally, we identified potential subtype-specific therapeutic targets, including CCNE1, EPHA3, RNF43, ROS1, and RSPO2 for subtype I and CDKN2A and RET for subtype II. Considering the need for potent diagnostic and therapeutic biomarkers for eMPM, we are anticipating that our findings will help both in exploring underlying mechanisms in the development of eMPM and in designing targeted therapy for eMPM.
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Affiliation(s)
- Umair Ali Khan Saddozai
- Department of Preventive Medicine, Institute of Bioinformatics Center, Henan Provincial Engineering Center for Tumor Molecular Medicine, School of Basic Medical Sciences, Henan University, Kaifeng 475004, China
| | - Fengling Wang
- Department of Preventive Medicine, Institute of Bioinformatics Center, Henan Provincial Engineering Center for Tumor Molecular Medicine, School of Basic Medical Sciences, Henan University, Kaifeng 475004, China
| | - Saadullah Khattak
- Department of Preventive Medicine, Institute of Bioinformatics Center, Henan Provincial Engineering Center for Tumor Molecular Medicine, School of Basic Medical Sciences, Henan University, Kaifeng 475004, China
| | - Muhammad Usman Akbar
- Gomal Center of Biochemistry and Biotechnology, Gomal University, Dera Ismail Khan 29050, Pakistan
| | - Muhammad Badar
- Gomal Center of Biochemistry and Biotechnology, Gomal University, Dera Ismail Khan 29050, Pakistan
| | - Nazeer Hussain Khan
- Department of Preventive Medicine, Institute of Bioinformatics Center, Henan Provincial Engineering Center for Tumor Molecular Medicine, School of Basic Medical Sciences, Henan University, Kaifeng 475004, China
| | - Lu Zhang
- Department of Preventive Medicine, Institute of Bioinformatics Center, Henan Provincial Engineering Center for Tumor Molecular Medicine, School of Basic Medical Sciences, Henan University, Kaifeng 475004, China
| | - Wan Zhu
- Department of Anesthesia, Stanford University, 300 Pasteur Drive, Stanford, CA 94305, USA
| | - Longxiang Xie
- Department of Preventive Medicine, Institute of Bioinformatics Center, Henan Provincial Engineering Center for Tumor Molecular Medicine, School of Basic Medical Sciences, Henan University, Kaifeng 475004, China
| | - Yongqiang Li
- Department of Preventive Medicine, Institute of Bioinformatics Center, Henan Provincial Engineering Center for Tumor Molecular Medicine, School of Basic Medical Sciences, Henan University, Kaifeng 475004, China
| | - Xinying Ji
- Department of Preventive Medicine, Institute of Bioinformatics Center, Henan Provincial Engineering Center for Tumor Molecular Medicine, School of Basic Medical Sciences, Henan University, Kaifeng 475004, China
- Correspondence: (X.J.); (X.G.)
| | - Xiangqian Guo
- Department of Preventive Medicine, Institute of Bioinformatics Center, Henan Provincial Engineering Center for Tumor Molecular Medicine, School of Basic Medical Sciences, Henan University, Kaifeng 475004, China
- Correspondence: (X.J.); (X.G.)
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9
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Guo X, Chen H, Zhou Y, Shen L, Wu S, Chen Y. Cyclin-dependent kinase inhibition and its intersection with immunotherapy in breast cancer: more than CDK4/6 inhibition. Expert Opin Investig Drugs 2022; 31:933-944. [PMID: 35786092 DOI: 10.1080/13543784.2022.2097067] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022]
Abstract
INTRODUCTION Cyclin-dependent kinase (CDK) 4/6 inhibitors (CDK4/6i) have had clinical success in treating hormone receptor-positive, human epidermal growth factor receptor 2-negative metastatic breast cancer. Notably, CDK4/6i have expanded to the neoadjuvant setting for early breast cancer and other cancer types and potently synergize with immunotherapy. Other CDKs, including CDK7, CDK9, and CDK12/13, mainly function in transcriptional processes as well as cell cycle regulation, RNA splicing, and DNA damage response. Inhibiting these CDKs aids in suppressing tumors, reversing drug resistance, increasing drug sensitivity, and enhancing anti-tumor immunity in breast cancer. AREAS COVERED We reviewed the applications of CDK4/6i, CDK7i, CDK9i and CDK12/13i for various breast cancer subtypes and their potentials for combination with immunotherapy. A literature search of PubMed, Embase, and Web of Science was conducted in April 2022. EXPERT OPINION The use of CDK4/6i represents a major milestone in breast cancer treatment. Moreover, transcription-related CDKs play critical roles in tumor development and are promising therapeutic targets for breast cancer. Some relevant clinical studies are underway. More specific and efficient CDKis will undoubtedly be developed and clinically tested. Characterization of their immune-priming effects will promote the development of combination therapies consisting of CDKi and immunotherapy.
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Affiliation(s)
- Xianan Guo
- Department of Breast Surgery and Oncology, Key Laboratory of Cancer Prevention and Intervention, Ministry of Education, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
| | - Huihui Chen
- Department of Breast Surgery and Oncology, Key Laboratory of Cancer Prevention and Intervention, Ministry of Education, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
| | - Yunxiang Zhou
- Department of Breast Surgery and Oncology, Key Laboratory of Cancer Prevention and Intervention, Ministry of Education, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
| | - Lu Shen
- Department of Breast Surgery and Oncology, Key Laboratory of Cancer Prevention and Intervention, Ministry of Education, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
| | - Shijie Wu
- Department of Breast Surgery and Oncology, Key Laboratory of Cancer Prevention and Intervention, Ministry of Education, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
| | - Yiding Chen
- Department of Breast Surgery and Oncology, Key Laboratory of Cancer Prevention and Intervention, Ministry of Education, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
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10
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Dewi C, Fristiohady A, Amalia R, Khairul Ikram NK, Ibrahim S, Muchtaridi M. Signaling Pathways and Natural Compounds in Triple-Negative Breast Cancer Cell Line. MOLECULES (BASEL, SWITZERLAND) 2022; 27:molecules27123661. [PMID: 35744786 PMCID: PMC9227697 DOI: 10.3390/molecules27123661] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/24/2022] [Revised: 05/25/2022] [Accepted: 05/30/2022] [Indexed: 11/16/2022]
Abstract
Triple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancer, having a poor prognosis and rapid metastases. TNBC is characterized by the absence of estrogen, progesterone, and human epidermal growth receptor-2 (HER2) expressions and has a five-year survival rate. Compared to other breast cancer subtypes, TNBC patients only respond to conventional chemotherapies, and even then, with limited success. Shortages of chemotherapeutic medication can lead to resistance, pressured index therapy, non-selectivity, and severe adverse effects. Finding targeted treatments for TNBC is difficult owing to the various features of cancer. Hence, identifying the most effective molecular targets in TNBC pathogenesis is essential for predicting response to targeted therapies and preventing TNBC cell metastases. Nowadays, natural compounds have gained attention as TNBC treatments, and have offered new strategies for solving drug resistance. Here, we report a systematic review using the database from Pubmed, Science Direct, MDPI, BioScince, Springer, and Nature for articles screening from 2003 to 2022. This review analyzes relevant signaling pathways and the prospect of utilizing natural compounds as a therapeutic agent to improve TNBC treatments in the future.
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Affiliation(s)
- Citra Dewi
- Department of Pharmaceutical Analysis and Medicinal Chemistry, Faculty of Pharmacy, Universitas Padjadjaran, Sumedang 45363, Indonesia;
- Pharmacy Department, Faculty of Science and Technology, Mandala Waluya University, Kendari 93561, Indonesia
| | - Adryan Fristiohady
- Faculty of Pharmacy, Halu Oleo University, Kampus Hijau Bumi Tridharma, Kendari 93232, Indonesia;
| | - Riezki Amalia
- Department of Pharmacology and Clinical Pharmacy, Faculty of Pharmacy, Universitas Padjadjaran, Sumedang 45363, Indonesia;
| | - Nur Kusaira Khairul Ikram
- Institute of Biological Sciences, Faculty of Science, Universiti Malaya, Kuala Lumpur 50603, Malaysia;
| | - Sugeng Ibrahim
- Department of Molecular Biology, Faculty of Medicine, Universitas Katolik Soegijapranata, Semarang 50234, Indonesia;
| | - Muchtaridi Muchtaridi
- Department of Pharmaceutical Analysis and Medicinal Chemistry, Faculty of Pharmacy, Universitas Padjadjaran, Sumedang 45363, Indonesia;
- Correspondence:
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11
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Mehlich D, Marusiak AA. Kinase inhibitors for precision therapy of triple-negative breast cancer: Progress, challenges, and new perspectives on targeting this heterogeneous disease. Cancer Lett 2022; 547:215775. [DOI: 10.1016/j.canlet.2022.215775] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2022] [Revised: 05/20/2022] [Accepted: 05/31/2022] [Indexed: 12/21/2022]
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12
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Shi Z, Tian L, Qiang T, Li J, Xing Y, Ren X, Liu C, Liang C. From Structure Modification to Drug Launch: A Systematic Review of the Ongoing Development of Cyclin-Dependent Kinase Inhibitors for Multiple Cancer Therapy. J Med Chem 2022; 65:6390-6418. [PMID: 35485642 DOI: 10.1021/acs.jmedchem.1c02064] [Citation(s) in RCA: 31] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Herein, we discuss more than 50 cyclin-dependent kinase (CDK) inhibitors that have been approved or have undergone clinical trials and their therapeutic application in multiple cancers. This review discusses the design strategies, structure-activity relationships, and efficacy performances of these selective or nonselective CDK inhibitors. The theoretical basis of early broad-spectrum CDK inhibitors is similar to the scope of chemotherapy, but because their toxicity is greater than the benefit, there is no clinical therapeutic window. The notion that selective CDK inhibitors have a safer therapeutic potential than pan-CDK inhibitors has been widely recognized during the research process. Four CDK4/6 inhibitors have been approved for the treatment of breast cancer or for prophylactic administration during chemotherapy to protect bone marrow and immune system function. Furthermore, the emerging strategies in the field of CDK inhibitors are summarized briefly, and CDKs continue to be widely pursued as emerging anticancer drug targets for drug discovery.
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Affiliation(s)
- Zhenfeng Shi
- Department of Urology Surgery Center, The People's Hospital of Xinjiang Uyghur Autonomous Region, Urumqi 830002, P. R. China
| | - Lei Tian
- College of Bioresources Chemical and Materials Engineering, Shaanxi University of Science & Technology, Xi'an 710021, P. R. China.,Faculty of Pharmacy, Shaanxi University of Science & Technology, Xi'an 710021, P. R. China
| | - Taotao Qiang
- College of Bioresources Chemical and Materials Engineering, Shaanxi University of Science & Technology, Xi'an 710021, P. R. China
| | - Jingyi Li
- Faculty of Pharmacy, Shaanxi University of Science & Technology, Xi'an 710021, P. R. China
| | - Yue Xing
- Faculty of Pharmacy, Shaanxi University of Science & Technology, Xi'an 710021, P. R. China
| | - Xiaodong Ren
- Medical College, Guizhou University, Guiyang 550025, P. R. China
| | - Chang Liu
- Zhuhai Jinan Selenium Source Nanotechnology Co., Ltd., Zhuhai 519030, P. R. China
| | - Chengyuan Liang
- Faculty of Pharmacy, Shaanxi University of Science & Technology, Xi'an 710021, P. R. China
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13
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Effective targeting of breast cancer stem cells by combined inhibition of Sam68 and Rad51. Oncogene 2022; 41:2196-2209. [PMID: 35217791 PMCID: PMC8993694 DOI: 10.1038/s41388-022-02239-4] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2021] [Revised: 01/07/2022] [Accepted: 02/09/2022] [Indexed: 12/17/2022]
Abstract
Breast cancer (BC) is the second cause of cancer-related deceases in the worldwide female population. Despite the successful treatment advances, 25% of BC develops resistance to current therapeutic regimens, thereby remaining a major hurdle for patient management. Current therapies, targeting the molecular events underpinning the adaptive resistance, still require effort to improve BC treatment. Using BC sphere cells (BCSphCs) as a model, here we showed that BC stem-like cells express high levels of Myc, which requires the presence of the multifunctional DNA/RNA binding protein Sam68 for the DNA-damage repair. Analysis of a cohort of BC patients displayed that Sam68 is an independent negative factor correlated with the progression of the disease. Genetic inhibition of Sam68 caused a defect in PARP-induced PAR chain synthesis upon DNA-damaging insults, resulting in cell death of TNBC cells. In contrast, BC stem-like cells were able to survive due to an upregulation of Rad51. Importantly, the inhibition of Rad51 showed synthetic lethal effect with the silencing of Sam68, hampering the cell viability of patient-derived BCSphCs and stabilizing the growth of tumor xenografts, including those TNBC carrying BRCA mutation. Moreover, the analysis of Myc, Sam68 and Rad51 expression demarcated a signature of a poor outcome in a large cohort of BC patients. Thus, our findings suggest the importance of targeting Sam68-PARP1 axis and Rad51 as potential therapeutic candidates to counteract the expansion of BC cells with an aggressive phenotype.
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14
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Li W, Zhang J, Wang M, Dong R, Zhou X, Zheng X, Sun L. Pyrimidine-fused Dinitrogenous Penta-heterocycles as a Privileged Scaffold for Anti-Cancer Drug Discovery. Curr Top Med Chem 2022; 22:284-304. [PMID: 35021973 DOI: 10.2174/1568026622666220111143949] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2021] [Revised: 12/30/2021] [Accepted: 12/30/2021] [Indexed: 11/22/2022]
Abstract
Pyrimidine-fused derivatives that are the inextricable part of DNA and RNA play a key role in the normal life cycle of cells. Pyrimidine-fused dinitrogenous penta-heterocycles including pyrazolopyrimidines and imidazopyrimidines is a special class of pyrimidine-fused compounds contributing to an important portion in anti-cancer drug discovery, which have been discovered as core structure for promising anti-cancer agents used in clinic or clinical evaluations. Pyrimidine-fused dinitrogenous penta-heterocycles have become one privileged scaffold for anti-cancer drug discovery. This review consists of the recent progress of pyrimidine-fused dinitrogenous penta-heterocycles as anti-cancer agents and their synthetic strategies. In addition, this review also summarizes some key structure-activity relationships (SARs) of pyrimidine-fused dinitrogenous penta-heterocycle derivatives as anti-cancer agents.
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Affiliation(s)
- Wen Li
- Jiangsu Key Laboratory of Drug Design & Optimization, Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing 210009, PR China
| | - Jinyang Zhang
- Jiangsu Key Laboratory of Drug Design & Optimization, Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing 210009, PR China
| | - Min Wang
- Jiangsu Key Laboratory of Drug Design & Optimization, Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing 210009, PR China
| | - Ru Dong
- Jiangsu Key Laboratory of Drug Design & Optimization, Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing 210009, PR China
| | - Xin Zhou
- Jiangsu Key Laboratory of Drug Design & Optimization, Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing 210009, PR China
| | - Xin Zheng
- Jiangsu Key Laboratory of Drug Design & Optimization, Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing 210009, PR China
| | - Liping Sun
- Jiangsu Key Laboratory of Drug Design & Optimization, Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing 210009, PR China
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15
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Apostolidi M, Vathiotis IA, Muthusamy V, Gaule P, Gassaway BM, Rimm DL, Rinehart J. Targeting Pyruvate Kinase M2 Phosphorylation Reverses Aggressive Cancer Phenotypes. Cancer Res 2021; 81:4346-4359. [PMID: 34185676 PMCID: PMC8373815 DOI: 10.1158/0008-5472.can-20-4190] [Citation(s) in RCA: 38] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2020] [Revised: 05/05/2021] [Accepted: 06/18/2021] [Indexed: 01/30/2023]
Abstract
Triple-negative breast cancer (TNBC) is the most aggressive breast cancer subtype with low survival rate and a lack of biomarkers and targeted treatments. Here, we target pyruvate kinase M2 (PKM2), a key metabolic component of oncogenesis. In patients with TNBC, PKM2pS37 was identified as a prominent phosphoprotein corresponding to the aggressive breast cancer phenotype that showed a characteristic nuclear staining pattern and prognostic value. Phosphorylation of PKM2 at S37 was connected with a cyclin-dependent kinase (CDK) pathway in TNBC cells. In parallel, pyruvate kinase activator TEPP-46 bound PKM2pS37 and reduced its nuclear localization. In a TNBC mouse xenograft model, treatment with either TEPP-46 or the potent CDK inhibitor dinaciclib reduced tumor growth and diminished PKM2pS37. Combinations of dinaciclib with TEPP-46 reduced cell invasion, impaired redox balance, and triggered cancer cell death. Collectively, these data support an approach to identify PKM2pS37-positive TNBC and target the PKM2 regulatory axis as a potential treatment. SIGNIFICANCE: PKM2 phosphorylation marks aggressive breast cancer cell phenotypes and targeting PKM2pS37 could be an effective therapeutic approach for treating triple-negative breast cancer.
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Affiliation(s)
- Maria Apostolidi
- Department of Cellular and Molecular Physiology, Yale University School of Medicine, New Haven, Connecticut
- Systems Biology Institute, Yale University, West Haven, Connecticut
| | - Ioannis A Vathiotis
- Department of Pathology, Yale University School of Medicine, New Haven, Connecticut
| | - Viswanathan Muthusamy
- Yale Center for Precision Cancer Modeling, Yale University School of Medicine, New Haven, Connecticut
- Yale Cancer Center, Yale School of Medicine, New Haven, Connecticut
| | - Patricia Gaule
- Specialized Translational Services Laboratory, Department of Pathology, Yale University School of Medicine, New Haven, Connecticut
| | - Brandon M Gassaway
- Department of Cellular and Molecular Physiology, Yale University School of Medicine, New Haven, Connecticut
- Systems Biology Institute, Yale University, West Haven, Connecticut
| | - David L Rimm
- Department of Pathology, Yale University School of Medicine, New Haven, Connecticut
- Yale Cancer Center, Yale School of Medicine, New Haven, Connecticut
| | - Jesse Rinehart
- Department of Cellular and Molecular Physiology, Yale University School of Medicine, New Haven, Connecticut.
- Systems Biology Institute, Yale University, West Haven, Connecticut
- Yale Cancer Center, Yale School of Medicine, New Haven, Connecticut
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16
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Damaskos C, Garmpis N, Garmpi A, Nikolettos K, Sarantis P, Georgakopoulou VE, Nonni A, Schizas D, Antoniou EA, Karamouzis MV, Nikolettos N, Kontzoglou K, Patsouras A, Voutyritsa E, Syllaios A, Koustas E, Trakas N, Dimitroulis D. Investigational Drug Treatments for Triple-Negative Breast Cancer. J Pers Med 2021; 11:652. [PMID: 34357119 PMCID: PMC8303312 DOI: 10.3390/jpm11070652] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2021] [Revised: 06/25/2021] [Accepted: 07/08/2021] [Indexed: 02/05/2023] Open
Abstract
Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer (BC) and accounts for 10-20% of cases. Due to the lack of expression of several receptors, hormone therapy is largely ineffective for treatment purposes. Nevertheless, TNBC often responds very well to chemotherapy, which constitutes the most often recommended treatment. New beneficial targeted therapies are important to be investigated in order to achieve enhanced outcomes in patients with TNBC. This review will focus on recent therapeutic innovations for TNBC, focusing on various inhibitors such as phosphoinositide 3-kinase (PI3K) pathway inhibitors, poly-ADP-ribosyl polymerase (PARP) inhibitors, aurora kinase inhibitors, histone deacetylase inhibitors (HDACIs), and immune checkpoint inhibitors.
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Affiliation(s)
- Christos Damaskos
- Renal Transplantation Unit, Laiko General Hospital, 11527 Athens, Greece
- N.S. Christeas Laboratory of Experimental Surgery and Surgical Research, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece; (N.G.); (K.N.); (E.A.A.); (K.K.); (A.P.); (E.V.)
| | - Nikolaos Garmpis
- N.S. Christeas Laboratory of Experimental Surgery and Surgical Research, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece; (N.G.); (K.N.); (E.A.A.); (K.K.); (A.P.); (E.V.)
- Second Department of Propedeutic Surgery, Laiko General Hospital, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece;
| | - Anna Garmpi
- First Department of Propedeutic Internal Medicine, Laiko General Hospital, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece;
| | - Konstantinos Nikolettos
- N.S. Christeas Laboratory of Experimental Surgery and Surgical Research, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece; (N.G.); (K.N.); (E.A.A.); (K.K.); (A.P.); (E.V.)
| | - Panagiotis Sarantis
- Molecular Oncology Unit, Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece; (P.S.); (M.V.K.); (E.K.)
| | | | - Afroditi Nonni
- First Department of Pathology, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece;
| | - Dimitrios Schizas
- First Department of Surgery, Laiko General Hospital, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece; (D.S.); (A.S.)
| | - Efstathios A. Antoniou
- N.S. Christeas Laboratory of Experimental Surgery and Surgical Research, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece; (N.G.); (K.N.); (E.A.A.); (K.K.); (A.P.); (E.V.)
- Second Department of Propedeutic Surgery, Laiko General Hospital, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece;
| | - Michalis V. Karamouzis
- Molecular Oncology Unit, Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece; (P.S.); (M.V.K.); (E.K.)
| | - Nikos Nikolettos
- Obstetric-Gynecologic Clinic, Medical School, Democritus University of Thrace, 68100 Alexandroupolis, Greece;
| | - Konstantinos Kontzoglou
- N.S. Christeas Laboratory of Experimental Surgery and Surgical Research, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece; (N.G.); (K.N.); (E.A.A.); (K.K.); (A.P.); (E.V.)
- Second Department of Propedeutic Surgery, Laiko General Hospital, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece;
| | - Alexandros Patsouras
- N.S. Christeas Laboratory of Experimental Surgery and Surgical Research, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece; (N.G.); (K.N.); (E.A.A.); (K.K.); (A.P.); (E.V.)
| | - Errika Voutyritsa
- N.S. Christeas Laboratory of Experimental Surgery and Surgical Research, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece; (N.G.); (K.N.); (E.A.A.); (K.K.); (A.P.); (E.V.)
| | - Athanasios Syllaios
- First Department of Surgery, Laiko General Hospital, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece; (D.S.); (A.S.)
| | - Evangelos Koustas
- Molecular Oncology Unit, Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece; (P.S.); (M.V.K.); (E.K.)
| | - Nikolaos Trakas
- Department of Biochemistry, Sismanogleio Hospital, 15126 Athens, Greece;
| | - Dimitrios Dimitroulis
- Second Department of Propedeutic Surgery, Laiko General Hospital, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece;
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17
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Suski JM, Braun M, Strmiska V, Sicinski P. Targeting cell-cycle machinery in cancer. Cancer Cell 2021; 39:759-778. [PMID: 33891890 PMCID: PMC8206013 DOI: 10.1016/j.ccell.2021.03.010] [Citation(s) in RCA: 302] [Impact Index Per Article: 75.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/24/2020] [Revised: 02/09/2021] [Accepted: 03/26/2021] [Indexed: 12/19/2022]
Abstract
Abnormal activity of the core cell-cycle machinery is seen in essentially all tumor types and represents a driving force of tumorigenesis. Recent studies revealed that cell-cycle proteins regulate a wide range of cellular functions, in addition to promoting cell division. With the clinical success of CDK4/6 inhibitors, it is becoming increasingly clear that targeting individual cell-cycle components may represent an effective anti-cancer strategy. Here, we discuss the potential of inhibiting different cell-cycle proteins for cancer therapy.
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Affiliation(s)
- Jan M Suski
- Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Genetics, Blavatnik Institute, Harvard Medical School, Boston, MA 02115, USA
| | - Marcin Braun
- Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Genetics, Blavatnik Institute, Harvard Medical School, Boston, MA 02115, USA; Department of Pathology, Chair of Oncology, Medical University of Lodz, 92-213 Lodz, Poland
| | - Vladislav Strmiska
- Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Genetics, Blavatnik Institute, Harvard Medical School, Boston, MA 02115, USA
| | - Piotr Sicinski
- Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Genetics, Blavatnik Institute, Harvard Medical School, Boston, MA 02115, USA.
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18
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Schoenwaelder N, Salewski I, Engel N, Krause M, Schneider B, Müller M, Riess C, Lemcke H, Skorska A, Grosse-Thie C, Junghanss C, Maletzki C. The Individual Effects of Cyclin-Dependent Kinase Inhibitors on Head and Neck Cancer Cells-A Systematic Analysis. Cancers (Basel) 2021; 13:cancers13102396. [PMID: 34063457 PMCID: PMC8157193 DOI: 10.3390/cancers13102396] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2021] [Revised: 04/07/2021] [Accepted: 05/11/2021] [Indexed: 12/24/2022] Open
Abstract
Cyclin-dependent kinase inhibitors (CDKi´s) display cytotoxic activity against different malignancies, including head and neck squamous cell carcinomas (HNSCC). By coordinating the DNA damage response, these substances may be combined with cytostatics to enhance cytotoxicity. Here, we investigated the influence of different CDKi´s (palbociclib, dinaciclib, THZ1) on two HNSCC cell lines in monotherapy and combination therapy with clinically-approved drugs (5-FU, Cisplatin, cetuximab). Apoptosis/necrosis, cell cycle, invasiveness, senescence, radiation-induced γ-H2AX DNA double-strand breaks, and effects on the actin filament were studied. Furthermore, the potential to increase tumor immunogenicity was assessed by analyzing Calreticulin translocation and immune relevant surface markers. Finally, an in vivo mouse model was used to analyze the effect of dinaciclib and Cisplatin combination therapy. Dinaciclib, palbociclib, and THZ1 displayed anti-neoplastic activity after low-dose treatment, while the two latter substances slightly enhanced radiosensitivity. Dinaciclib decelerated wound healing, decreased invasiveness, and induced MHC-I, accompanied by high amounts of surface-bound Calreticulin. Numbers of early and late apoptotic cells increased initially (24 h), while necrosis dominated afterward. Antitumoral effects of the selective CDKi palbociclib were weaker, but combinations with 5-FU potentiated effects of the monotherapy. Additionally, CDKi and CDKi/chemotherapy combinations induced MHC I, indicative of enhanced immunogenicity. The in vivo studies revealed a cell line-specific response with best tumor growth control in the combination approach. Global acting CDKi's should be further investigated as targeting agents for HNSCC, either individually or in combination with selected drugs. The ability of dinaciclib to increase the immunogenicity of tumor cells renders this substance a particularly interesting candidate for immune-based oncological treatment regimens.
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Affiliation(s)
- Nina Schoenwaelder
- Department of Internal Medicine, Medical Clinic III—Hematology, Oncology, Palliative Medicine, University Medical Center Rostock, 18057 Rostock, Germany; (I.S.); (M.K.); (C.R.); (C.G.-T.); (C.J.); (C.M.)
- Correspondence: ; Tel.: +49-381-494-5764
| | - Inken Salewski
- Department of Internal Medicine, Medical Clinic III—Hematology, Oncology, Palliative Medicine, University Medical Center Rostock, 18057 Rostock, Germany; (I.S.); (M.K.); (C.R.); (C.G.-T.); (C.J.); (C.M.)
| | - Nadja Engel
- Department of Oral and Maxillofacial Surgery, Facial Plastic Surgery, University Medical Center Rostock, 18057 Rostock, Germany;
| | - Mareike Krause
- Department of Internal Medicine, Medical Clinic III—Hematology, Oncology, Palliative Medicine, University Medical Center Rostock, 18057 Rostock, Germany; (I.S.); (M.K.); (C.R.); (C.G.-T.); (C.J.); (C.M.)
| | - Björn Schneider
- Institute of Pathology, University Medical Center Rostock, Strempelstr.14, 18057 Rostock, Germany;
| | - Michael Müller
- Core Facility for Cell Sorting & Cell Analysis, Laboratory for Clinical Immunology, University Medical Center Rostock, 18057 Rostock, Germany;
| | - Christin Riess
- Department of Internal Medicine, Medical Clinic III—Hematology, Oncology, Palliative Medicine, University Medical Center Rostock, 18057 Rostock, Germany; (I.S.); (M.K.); (C.R.); (C.G.-T.); (C.J.); (C.M.)
- University Children’s Hospital, Rostock University Medical Centre, 18057 Rostock, Germany
| | - Heiko Lemcke
- Department of Cardiac Surgery, Reference and Translation Center for Cardiac Stem Cell Therapy (RTC), University Medical Center Rostock, 18057 Rostock, Germany; (H.L.); (A.S.)
- Department of Cardiology, University Medical Center Rostock, 18059 Rostock, Germany
- Department Life, Light & Matter, Faculty of Interdisciplinary Research, University Rostock, 18059 Rostock, Germany
| | - Anna Skorska
- Department of Cardiac Surgery, Reference and Translation Center for Cardiac Stem Cell Therapy (RTC), University Medical Center Rostock, 18057 Rostock, Germany; (H.L.); (A.S.)
- Department of Cardiology, University Medical Center Rostock, 18059 Rostock, Germany
- Department Life, Light & Matter, Faculty of Interdisciplinary Research, University Rostock, 18059 Rostock, Germany
| | - Christina Grosse-Thie
- Department of Internal Medicine, Medical Clinic III—Hematology, Oncology, Palliative Medicine, University Medical Center Rostock, 18057 Rostock, Germany; (I.S.); (M.K.); (C.R.); (C.G.-T.); (C.J.); (C.M.)
| | - Christian Junghanss
- Department of Internal Medicine, Medical Clinic III—Hematology, Oncology, Palliative Medicine, University Medical Center Rostock, 18057 Rostock, Germany; (I.S.); (M.K.); (C.R.); (C.G.-T.); (C.J.); (C.M.)
| | - Claudia Maletzki
- Department of Internal Medicine, Medical Clinic III—Hematology, Oncology, Palliative Medicine, University Medical Center Rostock, 18057 Rostock, Germany; (I.S.); (M.K.); (C.R.); (C.G.-T.); (C.J.); (C.M.)
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Agostinetto E, Eiger D, Punie K, de Azambuja E. Emerging Therapeutics for Patients with Triple-Negative Breast Cancer. Curr Oncol Rep 2021; 23:57. [PMID: 33763756 DOI: 10.1007/s11912-021-01038-6] [Citation(s) in RCA: 30] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/12/2021] [Indexed: 02/08/2023]
Abstract
PURPOSE OF REVIEW Triple negative breast cancer (TNBC) accounts for approximately 10-15% of all breast cancers and it is associated with a poor prognosis. However, recent new effective treatment strategies have improved its outcomes. The aim of this review is to provide an overview on the emerging therapeutics for TNBC, describing both previously approved therapies that are currently being repurposed, as well as new target therapies that may improve patient outcomes. RECENT FINDINGS Emerging therapies are forthcoming in TNBC's treatment landscape, including new post-neoadjuvant chemotherapy strategies, PARP inhibitors, immune checkpoint inhibitors, and antibody-drug conjugates. Combination of different therapies such as AKT/PI3K/mTOR-inhibitors, other immunotherapeutic agents, CDK-inhibitors, antiandrogens, antiangiogenics, and histone deacetylase inhibitors is under clinical investigation. The treatment landscape for TNBC is gradually evolving towards a more personalized approach with promising expectations.
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Affiliation(s)
- Elisa Agostinetto
- Academic Trials Promoting Team, Institut Jules Bordet and l'Université Libre de Bruxelles (U.L.B), Rue Héger-Bordet 1, 1000, Brussels, Belgium.,Department of Medical Oncology and Hematology, Humanitas Clinical and Research Center - IRCCS, Humanitas Cancer Center, via Manzoni 56, 20089, Rozzano, Milan, Italy
| | - Daniel Eiger
- Academic Trials Promoting Team, Institut Jules Bordet and l'Université Libre de Bruxelles (U.L.B), Rue Héger-Bordet 1, 1000, Brussels, Belgium
| | - Kevin Punie
- Department of General Medical Oncology and Multidisciplinary Breast Centre, Leuven Cancer Institute, University Hospitals Leuven, Leuven, Belgium
| | - Evandro de Azambuja
- Academic Trials Promoting Team, Institut Jules Bordet and l'Université Libre de Bruxelles (U.L.B), Rue Héger-Bordet 1, 1000, Brussels, Belgium.
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20
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Qiu X, Li Y, Yu B, Ren J, Huang H, Wang M, Ding H, Li Z, Wang J, Bian J. Discovery of selective CDK9 degraders with enhancing antiproliferative activity through PROTAC conversion. Eur J Med Chem 2021; 211:113091. [PMID: 33338869 DOI: 10.1016/j.ejmech.2020.113091] [Citation(s) in RCA: 53] [Impact Index Per Article: 13.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2020] [Revised: 11/05/2020] [Accepted: 12/05/2020] [Indexed: 10/22/2022]
Abstract
Cyclin-dependent kinase 9 (CDK9) is an increasingly important potential cancer treatment target. Nowadays, developing selective CDK9 inhibitors has been extremely challenging as its ATP-binding sites are similar with other CDKs. Here, we report that the CDK9 inhibitor BAY-1143572 is converted into a series of proteolysis targeting chimeras (PROTACs) which leads to several compounds inducing the degradation of CDK9 in acute myeloid leukemia cells at a low nanomolar concentration. In addition, the most potent PROTAC molecule B03 could inhibit cell growth more effectively than warhead alone, with little inhibition of other kinases. This enhanced antiproliferative activity is mediated by a slight increase in kinase inhibitory activity and an increase in the level of apoptosis induction. Moreover, B03 could induce the degradation of CDK9 in vivo. Our work provides evidence that B03 represents a lead for further development and that CDK9 degradation is a potential valuable therapeutic strategy in acute myeloid leukemia.
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Affiliation(s)
- Xiaqiu Qiu
- State Key Laboratory of Natural Medicines and Jiang Su Key Laboratory of Drug Design and Optimization, Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing, 210009, China
| | - Yuanqing Li
- State Key Laboratory of Drug Research, CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai, 201203, China
| | - Bin Yu
- State Key Laboratory of Natural Medicines and Jiang Su Key Laboratory of Drug Design and Optimization, Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing, 210009, China
| | - Jie Ren
- State Key Laboratory of Natural Medicines and Jiang Su Key Laboratory of Drug Design and Optimization, Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing, 210009, China
| | - Huidan Huang
- School of Pharmacy, Wannan Medical College, Wuhu, 241002, PR China.
| | - Min Wang
- State Key Laboratory of Natural Medicines and Jiang Su Key Laboratory of Drug Design and Optimization, Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing, 210009, China
| | - Hong Ding
- State Key Laboratory of Drug Research, CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai, 201203, China
| | - Zhiyu Li
- State Key Laboratory of Natural Medicines and Jiang Su Key Laboratory of Drug Design and Optimization, Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing, 210009, China
| | - Jubo Wang
- State Key Laboratory of Natural Medicines and Jiang Su Key Laboratory of Drug Design and Optimization, Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing, 210009, China
| | - Jinlei Bian
- State Key Laboratory of Natural Medicines and Jiang Su Key Laboratory of Drug Design and Optimization, Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing, 210009, China.
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21
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Actin-like protein 6A/MYC/CDK2 axis confers high proliferative activity in triple-negative breast cancer. JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH : CR 2021; 40:56. [PMID: 33541412 PMCID: PMC7863242 DOI: 10.1186/s13046-021-01856-3] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/19/2020] [Accepted: 01/25/2021] [Indexed: 12/31/2022]
Abstract
Background Triple negative breast cancer (TNBC) is an aggressive subtype of breast cancer with high proliferative activity. TNBC tumors exhibit elevated MYC expression and altered expression of MYC regulatory genes, which are associated with tumor progression and poor prognosis; however, the underlying mechanisms by which MYC retains its high expression and mediates TNBC tumorigenesis require further exploration. Methods ACTL6A regulation of MYC and its target gene, CDK2, was defined using Co-IP, mass spectrometry and ChIP assays. To study the role of ACTL6A in TNBC, we performed soft-agar, colony formation, flow cytometry and tumor formation in nude mice. CDK2 inhibitor and paclitaxel were used in testing combination therapy in vitro and in vivo. Results ACTL6A bound MYC to suppress glycogen synthase kinase 3 beta (GSK3β)-induced phosphorylation on MYC T58, which inhibited ubiquitination of MYC and stabilized it. Moreover, ACTL6A promoted the recruitment of MYC and histone acetyltransferase KAT5 on CDK2 promoters, leading to hyperactivation of CDK2 transcription. ACTL6A overexpression promoted, while silencing ACTL6A suppressed cell proliferation and tumor growth in TNBC cells in vitro and in vivo, which was dependent on MYC signaling. Furthermore, co-therapy with paclitaxel and CDK2 inhibitor showed synergistic effects in tumor suppression. Notably, ACTL6A/MYC/CDK2 axis was specifically up-regulated in TNBC and high expression of ACTL6A was correlated to shorter survival in patients with TNBC. Conclusions These findings reveal a novel mechanism by which ACTL6A prolongs the retention of MYC in TNBC and suggest that pharmacological targeting ACTL6A/MYC/CDK2 axis might have therapeutic potential in patients with TNBC. Supplementary Information The online version contains supplementary material available at 10.1186/s13046-021-01856-3.
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Abstract
ABSTRACT Triple-negative breast cancer is increasingly recognized as a heterogeneous entity that can be categorized according to histologic, molecular, and clinical subtypes. While chemotherapy remains the backbone of treatment for this disease, there are now several available targeted agents including immunotherapy, poly(adenosine diphosphate-ribose) polymerase inhibitors, and most recently a Food and Drug Administration-approved antibody-drug conjugate sacituzumab govitecan-hziy as a third-line treatment of metastatic triple-negative breast cancer. We review several actionable targets for triple-negative breast cancer and describe promising nonimmunotherapeutic agents including cyclin-dependent kinase inhibitors, androgen receptor inhibitors, mitogen-activated protein kinase inhibitors, phosphoinositide 3-kinase inhibitors, AKT (also known as protein kinase B) inhibitors, and antibody-drug conjugates.
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23
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Dobiasova B, Mego M. Biomarkers for Inflammatory Breast Cancer: Diagnostic and Therapeutic Utility. BREAST CANCER-TARGETS AND THERAPY 2020; 12:153-163. [PMID: 33116817 PMCID: PMC7569067 DOI: 10.2147/bctt.s231502] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 08/25/2020] [Accepted: 10/03/2020] [Indexed: 12/11/2022]
Abstract
Inflammatory breast cancer (IBC) is a rare and highly aggressive subtype of advanced breast cancer. The aggressive behavior, resistance to chemotherapy, angiogenesis, and high metastatic potential are key intrinsic characteristics of IBC caused by many specific factors. Pathogenesis and behavior of IBC are closely related to tumor surrounding inflammatory and immune cells, blood vessels, and extracellular matrix, which are all components of the tumor microenvironment (TME). The tumor microenvironment has a crucial role in the local immune r09esponse. The communication between intrinsic and extrinsic components of IBC and the abundance of cytokines and chemokines in the TME strongly contribute to the aggressiveness and high angiogenic potential of this tumor. Critical modes of interaction are cytokine-mediated communication and direct intercellular contact between cancer cells and tumor microenvironment with a variety of pathway crosstalk. This review aimed to summarize current knowledge of predictive and prognostic biomarkers in IBC.
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Affiliation(s)
- Barbora Dobiasova
- 2 Department of Oncology, Comenius University, Faculty of Medicine, National Cancer Institute, Bratislava, Slovak Republic
| | - Michal Mego
- 2 Department of Oncology, Comenius University, Faculty of Medicine, National Cancer Institute, Bratislava, Slovak Republic
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24
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Zou Y, Ruan S, Jin L, Chen Z, Han H, Zhang Y, Jian Z, Lin Y, Shi N, Jin H. CDK1, CCNB1, and CCNB2 are Prognostic Biomarkers and Correlated with Immune Infiltration in Hepatocellular Carcinoma. Med Sci Monit 2020; 26:e925289. [PMID: 32863381 PMCID: PMC7482506 DOI: 10.12659/msm.925289] [Citation(s) in RCA: 78] [Impact Index Per Article: 15.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2020] [Accepted: 06/03/2020] [Indexed: 02/05/2023] Open
Abstract
BACKGROUND Orderly G2/M transition in the cell cycle is controlled by the cyclin-dependent kinase 1/cyclin B (CDK1/CCNB) complex. We aimed to comprehensively investigate the roles of CDK1, CCNB1, and CCNB2 via multi-omics analysis and their relationships with immune infiltration in hepatocellular carcinoma (HCC). MATERIAL AND METHODS The transcriptional data and the epigenetic and genetic alterations of CDK1, CCNB1, and CCNB2, as well as their impacts on prognosis in HCC patients, were identified using multiple databases. The correlations between expression of these genes and immune infiltration in HCC were then explored using the TIMER database. RESULTS Overall, mRNA expression of CDK1, CCNB1, and CCNB2 was up-regulated in various tumor tissues including HCC. Higher expression of these genes was associated with poorer prognosis in HCC patients. Lower promoter methylation of these genes might cause higher expression levels in tumor tissues of HCC. Genetic alterations and several methylated-CpG sites in these genes were significantly associated with survival. Notably, expression levels of CDK1, CCNB1, and CCNB2 were positively correlated with infiltrating levels of CD4⁺ T cells, CD8⁺ T cells, neutrophils, macrophages, and dendritic cells in HCC. In addition, significant correlations between the expression of these genes and various immune markers in HCC, such as PD-1, PDL-1, and CTLA-4, were also observed. CONCLUSIONS CDK1, CCNB1, and CCNB2 are potential prognostic biomarkers and associated with immune cell infiltration in HCC. The genes may be utilized to predict the reaction of immunotherapy. Combining inhibitors of these genes with immunotherapy may improve the survival time of HCC patients.
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Affiliation(s)
- Yiping Zou
- Department of General Surgery, Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences, School of Medicine, South China University of Technology, Guangzhou, Guangdong, P.R. China
- Shantou University Medical College, Shantou, Guangdong, P.R. China
| | - Shiye Ruan
- Department of General Surgery, Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences, School of Medicine, South China University of Technology, Guangzhou, Guangdong, P.R. China
| | - Liang Jin
- Department of General Surgery, Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences, School of Medicine, South China University of Technology, Guangzhou, Guangdong, P.R. China
| | - Zhihong Chen
- Department of General Surgery, Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences, School of Medicine, South China University of Technology, Guangzhou, Guangdong, P.R. China
| | - Hongwei Han
- Department of General Surgery, Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences, School of Medicine, South China University of Technology, Guangzhou, Guangdong, P.R. China
| | - Yuanpeng Zhang
- Department of General Surgery, Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences, School of Medicine, South China University of Technology, Guangzhou, Guangdong, P.R. China
| | - Zhixiang Jian
- Department of General Surgery, Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences, School of Medicine, South China University of Technology, Guangzhou, Guangdong, P.R. China
| | - Ye Lin
- Department of General Surgery, Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences, School of Medicine, South China University of Technology, Guangzhou, Guangdong, P.R. China
| | - Ning Shi
- Department of General Surgery, Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences, School of Medicine, South China University of Technology, Guangzhou, Guangdong, P.R. China
| | - Haosheng Jin
- Department of General Surgery, Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences, School of Medicine, South China University of Technology, Guangzhou, Guangdong, P.R. China
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Cytoplasmic Cyclin E Is an Independent Marker of Aggressive Tumor Biology and Breast Cancer-Specific Mortality in Women over 70 Years of Age. Cancers (Basel) 2020; 12:cancers12030712. [PMID: 32197318 PMCID: PMC7140020 DOI: 10.3390/cancers12030712] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2020] [Accepted: 03/15/2020] [Indexed: 01/16/2023] Open
Abstract
Multi-cohort analysis demonstrated that cytoplasmic cyclin E expression in primary breast tumors predicts aggressive disease. However, compared to their younger counterparts, older patients have favorable tumor biology and are less likely to die of breast cancer. Biomarkers therefore require interpretation in this specific context. Here, we assess data on cytoplasmic cyclin E from a UK cohort of older women alongside a panel of >20 biomarkers. Between 1973 and 2010, 813 women ≥70 years of age underwent initial surgery for early breast cancer, from which a tissue microarray was constructed (n = 517). Biomarker expression was assessed by immunohistochemistry. Multivariate analysis of breast cancer-specific survival was performed using Cox's proportional hazards. We found that cytoplasmic cyclin E was the only biological factor independently predictive of breast cancer-specific survival in this cohort of older women (hazard ratio (HR) = 6.23, 95% confidence interval (CI) = 1.93-20.14; p = 0.002). At ten years, 42% of older patients with cytoplasmic cyclin E-positive tumors had died of breast cancer versus 8% of negative cases (p < 0.0005). We conclude that cytoplasmic cyclin E is an exquisite marker of aggressive tumor biology in older women. Patients with cytoplasmic cyclin E-negative tumors are unlikely to die of breast cancer. These data have the potential to influence treatment strategy in older patients.
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26
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Saga of Mcl-1: regulation from transcription to degradation. Cell Death Differ 2020; 27:405-419. [PMID: 31907390 DOI: 10.1038/s41418-019-0486-3] [Citation(s) in RCA: 104] [Impact Index Per Article: 20.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2019] [Revised: 12/05/2019] [Accepted: 12/13/2019] [Indexed: 01/01/2023] Open
Abstract
The members of the Bcl-2 family are the central regulators of various cell death modalities. Some of these proteins contribute to apoptosis, while others counteract this type of programmed cell death, thus balancing cell demise and survival. A disruption of this balance leads to the development of various diseases, including cancer. Therefore, understanding the mechanisms that underlie the regulation of proteins of the Bcl-2 family is of great importance for biomedical research. Among the members of the Bcl-2 family, antiapoptotic protein Mcl-1 is characterized by a short half-life, which renders this protein highly sensitive to changes in its synthesis or degradation. Hence, the regulation of Mcl-1 is of particular scientific interest, and the study of Mcl-1 modulators could aid in the understanding of the mechanisms of disease development and the ways of their treatment. Here, we summarize the present knowledge regarding the regulation of Mcl-1, from transcription to degradation, focusing on aspects that have not yet been described in detail.
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27
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Ferraiuolo RM, Wagner KU. Regulation and New Treatment Strategies in Breast Cancer. JOURNAL OF LIFE SCIENCES (WESTLAKE VILLAGE, CALIF.) 2019; 1:23-38. [PMID: 32095785 PMCID: PMC7039658] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Subscribe] [Scholar Register] [Indexed: 06/10/2023]
Abstract
Breast cancer classifications are based on the presence or absence of estrogen receptor and progesterone receptor along with the overexpression or amplification of the Her2 receptor. Although the overall 5-year survival rate of breast cancer patients has increased due to the use of targeted therapies, a subset of patients can acquire resistance over time or are unresponsive when presented in the clinic. Novel therapies focusing on molecular pathways and cell cycle regulation currently being used in the clinic may lead to increased response in this subset of patients.
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Affiliation(s)
- Rosa-Maria Ferraiuolo
- Karmanos Cancer Institute at Wayne State University
School of Medicine, Detroit, MI 48202
| | - Kay-Uwe Wagner
- Karmanos Cancer Institute at Wayne State University
School of Medicine, Detroit, MI 48202
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28
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CDK2-mediated site-specific phosphorylation of EZH2 drives and maintains triple-negative breast cancer. Nat Commun 2019; 10:5114. [PMID: 31704972 PMCID: PMC6841924 DOI: 10.1038/s41467-019-13105-5] [Citation(s) in RCA: 61] [Impact Index Per Article: 10.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2018] [Accepted: 10/15/2019] [Indexed: 12/17/2022] Open
Abstract
Triple-negative breast cancer (TNBC), which lacks estrogen receptor α (ERα), progesterone receptor, and human epidermal growth factor receptor 2 (HER2) expression, is closely related to basal-like breast cancer. Previously, we and others report that cyclin E/cyclin-dependent kinase 2 (CDK2) phosphorylates enhancer of zeste homolog 2 (EZH2) at T416 (pT416-EZH2). Here, we show that transgenic expression of phospho-mimicking EZH2 mutant EZH2T416D in mammary glands leads to tumors with TNBC phenotype. Coexpression of EZH2T416D in mammary epithelia of HER2/Neu transgenic mice reprograms HER2-driven luminal tumors into basal-like tumors. Pharmacological inhibition of CDK2 or EZH2 allows re-expression of ERα and converts TNBC to luminal ERα-positive, rendering TNBC cells targetable by tamoxifen. Furthermore, the combination of either CDK2 or EZH2 inhibitor with tamoxifen effectively suppresses tumor growth and markedly improves the survival of the mice bearing TNBC tumors, suggesting that the mechanism-based combination therapy may be an alternative approach to treat TNBC. EZH2 phosphorylation by CDK2 promotes progression of triple-negative breast cancer (TNBC). Here, the authors show that this signaling axis downregulates ERα, and thus combinatorial blockade of CDK2 and EZH2 sensitizes TNBC cells to tamoxifen.
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29
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Nakhjavani M, Hardingham JE, Palethorpe HM, Price TJ, Townsend AR. Druggable Molecular Targets for the Treatment of Triple Negative Breast Cancer. J Breast Cancer 2019; 22:341-361. [PMID: 31598336 PMCID: PMC6769384 DOI: 10.4048/jbc.2019.22.e39] [Citation(s) in RCA: 38] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2019] [Accepted: 08/20/2019] [Indexed: 12/16/2022] Open
Abstract
Breast cancer (BC) is still the most common cancer among women worldwide. Amongst the subtypes of BC, triple negative breast cancer (TNBC) is characterized by deficient expression of estrogen, progesterone, and human epidermal growth factor receptor 2 receptors. These patients are therefore not given the option of targeted therapy and have worse prognosis as a result. Consequently, much research has been devoted to identifying specific molecular targets that can be utilized for targeted cancer therapy, thereby limiting the progression and metastasis of this invasive tumor, and improving patient outcomes. In this review, we have focused on the molecular targets in TNBC, categorizing these into targets within the immune system such as immune checkpoint modulators, intra-nuclear targets, intracellular targets, and cell surface targets. The aim of this review is to introduce and summarize the known targets and drugs under investigation in phase II or III clinical trials, while introducing additional possible targets for future drug development. This review brings a tangible benefit to cancer researchers who seek a comprehensive comparison of TNBC treatment options.
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Affiliation(s)
- Maryam Nakhjavani
- Molecular Oncology, Basil Hetzel Institute, The Queen Elizabeth Hospital, Woodville South, Australia.,Adelaide Medical School, University of Adelaide, Adelaide, Australia
| | - Jennifer E Hardingham
- Molecular Oncology, Basil Hetzel Institute, The Queen Elizabeth Hospital, Woodville South, Australia.,Adelaide Medical School, University of Adelaide, Adelaide, Australia
| | - Helen M Palethorpe
- Molecular Oncology, Basil Hetzel Institute, The Queen Elizabeth Hospital, Woodville South, Australia.,Adelaide Medical School, University of Adelaide, Adelaide, Australia
| | - Tim J Price
- Adelaide Medical School, University of Adelaide, Adelaide, Australia.,Medical Oncology, The Queen Elizabeth Hospital, Woodville South, Australia
| | - Amanda R Townsend
- Adelaide Medical School, University of Adelaide, Adelaide, Australia.,Medical Oncology, The Queen Elizabeth Hospital, Woodville South, Australia
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30
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Jung SY, Nam KY, Park JI, Song KH, Ahn J, Park JK, Um HD, Hwang SG, Choi SU, Song JY. Radiosensitizing Effect of Novel Phenylpyrimidine Derivatives on Human Lung Cancer Cells via Cell Cycle Perturbation. J Pharmacol Exp Ther 2019; 370:514-527. [PMID: 31253693 DOI: 10.1124/jpet.119.257717] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2019] [Accepted: 06/24/2019] [Indexed: 12/21/2022] Open
Abstract
Radiotherapy is one of the most common treatments for cancer, but radioresistance and injury to normal tissue are considered major obstacles to successful radiotherapy. Thus, there is an urgent need to develop radiosensitizers to improve the therapeutic outcomes of radiotherapy in cancer patients. Our previous efforts to identify novel radiosensitizers, using high-throughput screening targeting p53 and Nrf2 revealed a promising N-phenylpyrimidin-2-amine (PPA) lead compound. In the present study, 17 derivatives of this lead compound were examined, and it was found that 4-(4-fluorophenyl)-N-(4-nitrophenyl)-6-phenylpyrimidin-2-amine (PPA5), 4-((4-(4-fluorophenyl)pyrimidin-2-yl)amino)-3-methoxy-N-methyl -benzamide (PPA13), 4-((4-(4-fluorophenyl)pyrimidin-2-yl)amino)benzenesulfonamide (PPA14), 4-((4-(2-chlorophenyl)pyrimidin-2-yl)amino)benzenesulfonamide (PPA15), and 4-((4-(2-chlorophenyl)pyrimidin-2-yl)amino)-N-methylbenzamide (PPA17) inhibited cell viability by more than 50%, with a marked increase in the proportion of cells arrested at the G2/M phase of cell cycle. Among these compounds, PPA15 markedly increased the sub-G1 cell population and increased the levels of cyclin B1 and the phosphorylation levels of cyclin-dependent kinase (CDK) 1. Combined treatment with radiation and PPA14 or PPA15 significantly decreased clonogenic survival. An in vitro kinase assay revealed that PPA15 inhibited multiple CDKs involved in cell cycle regulation. Compared with drug or radiation treatment alone, combined treatment with PPA15 and radiation resulted in the suppression of A549 tumor growth in mice by 59.5% and 52.7%, respectively. Treatment with PPA15 alone directly inhibited tumor growth by 25.7%. These findings suggest that the novel pan CDK inhibitor, PPA15, may be a promising treatment to improve the effectiveness of radiotherapy for the treatment of cancer. SIGNIFICANCE STATEMENT: Several inhibitors of CDK have been successfully evaluated in combination with other chemotherapeutics in clinical trials, but negative side effects have partially restricted their clinical use. In this study, we identified a novel pan-CDK inhibitor to increase radiosensitivity, and we hope this work will encourage the development of promising small-molecule radiosensitizers.
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Affiliation(s)
- Seung-Youn Jung
- Division of Radiation Biomedical Research, Korea Institute of Radiological & Medical Sciences, Seoul, Republic of Korea (S.-Y.J., J.-I.P., K.-H.S., J.A., J.K.P., H.-D.U., S.-G.H., J.-Y.S.); Research Center, Pharos I&BT Co., Ltd., Anyang, Republic of Korea (K.-Y.N.); Graduate School of Pharmaceutical Sciences, College of Pharmacy, Ewha Womans University, Seoul, Republic of Korea (K.-H.S.); and Bio and Drug Discovery Division, Korea Research Institute of Chemical Technology, Daejeon, Republic of Korea (S.U.C.)
| | - Ky-Youb Nam
- Division of Radiation Biomedical Research, Korea Institute of Radiological & Medical Sciences, Seoul, Republic of Korea (S.-Y.J., J.-I.P., K.-H.S., J.A., J.K.P., H.-D.U., S.-G.H., J.-Y.S.); Research Center, Pharos I&BT Co., Ltd., Anyang, Republic of Korea (K.-Y.N.); Graduate School of Pharmaceutical Sciences, College of Pharmacy, Ewha Womans University, Seoul, Republic of Korea (K.-H.S.); and Bio and Drug Discovery Division, Korea Research Institute of Chemical Technology, Daejeon, Republic of Korea (S.U.C.)
| | - Jeong-In Park
- Division of Radiation Biomedical Research, Korea Institute of Radiological & Medical Sciences, Seoul, Republic of Korea (S.-Y.J., J.-I.P., K.-H.S., J.A., J.K.P., H.-D.U., S.-G.H., J.-Y.S.); Research Center, Pharos I&BT Co., Ltd., Anyang, Republic of Korea (K.-Y.N.); Graduate School of Pharmaceutical Sciences, College of Pharmacy, Ewha Womans University, Seoul, Republic of Korea (K.-H.S.); and Bio and Drug Discovery Division, Korea Research Institute of Chemical Technology, Daejeon, Republic of Korea (S.U.C.)
| | - Kyung-Hee Song
- Division of Radiation Biomedical Research, Korea Institute of Radiological & Medical Sciences, Seoul, Republic of Korea (S.-Y.J., J.-I.P., K.-H.S., J.A., J.K.P., H.-D.U., S.-G.H., J.-Y.S.); Research Center, Pharos I&BT Co., Ltd., Anyang, Republic of Korea (K.-Y.N.); Graduate School of Pharmaceutical Sciences, College of Pharmacy, Ewha Womans University, Seoul, Republic of Korea (K.-H.S.); and Bio and Drug Discovery Division, Korea Research Institute of Chemical Technology, Daejeon, Republic of Korea (S.U.C.)
| | - Jiyeon Ahn
- Division of Radiation Biomedical Research, Korea Institute of Radiological & Medical Sciences, Seoul, Republic of Korea (S.-Y.J., J.-I.P., K.-H.S., J.A., J.K.P., H.-D.U., S.-G.H., J.-Y.S.); Research Center, Pharos I&BT Co., Ltd., Anyang, Republic of Korea (K.-Y.N.); Graduate School of Pharmaceutical Sciences, College of Pharmacy, Ewha Womans University, Seoul, Republic of Korea (K.-H.S.); and Bio and Drug Discovery Division, Korea Research Institute of Chemical Technology, Daejeon, Republic of Korea (S.U.C.)
| | - Jong Kuk Park
- Division of Radiation Biomedical Research, Korea Institute of Radiological & Medical Sciences, Seoul, Republic of Korea (S.-Y.J., J.-I.P., K.-H.S., J.A., J.K.P., H.-D.U., S.-G.H., J.-Y.S.); Research Center, Pharos I&BT Co., Ltd., Anyang, Republic of Korea (K.-Y.N.); Graduate School of Pharmaceutical Sciences, College of Pharmacy, Ewha Womans University, Seoul, Republic of Korea (K.-H.S.); and Bio and Drug Discovery Division, Korea Research Institute of Chemical Technology, Daejeon, Republic of Korea (S.U.C.)
| | - Hong-Duck Um
- Division of Radiation Biomedical Research, Korea Institute of Radiological & Medical Sciences, Seoul, Republic of Korea (S.-Y.J., J.-I.P., K.-H.S., J.A., J.K.P., H.-D.U., S.-G.H., J.-Y.S.); Research Center, Pharos I&BT Co., Ltd., Anyang, Republic of Korea (K.-Y.N.); Graduate School of Pharmaceutical Sciences, College of Pharmacy, Ewha Womans University, Seoul, Republic of Korea (K.-H.S.); and Bio and Drug Discovery Division, Korea Research Institute of Chemical Technology, Daejeon, Republic of Korea (S.U.C.)
| | - Sang-Gu Hwang
- Division of Radiation Biomedical Research, Korea Institute of Radiological & Medical Sciences, Seoul, Republic of Korea (S.-Y.J., J.-I.P., K.-H.S., J.A., J.K.P., H.-D.U., S.-G.H., J.-Y.S.); Research Center, Pharos I&BT Co., Ltd., Anyang, Republic of Korea (K.-Y.N.); Graduate School of Pharmaceutical Sciences, College of Pharmacy, Ewha Womans University, Seoul, Republic of Korea (K.-H.S.); and Bio and Drug Discovery Division, Korea Research Institute of Chemical Technology, Daejeon, Republic of Korea (S.U.C.)
| | - Sang Un Choi
- Division of Radiation Biomedical Research, Korea Institute of Radiological & Medical Sciences, Seoul, Republic of Korea (S.-Y.J., J.-I.P., K.-H.S., J.A., J.K.P., H.-D.U., S.-G.H., J.-Y.S.); Research Center, Pharos I&BT Co., Ltd., Anyang, Republic of Korea (K.-Y.N.); Graduate School of Pharmaceutical Sciences, College of Pharmacy, Ewha Womans University, Seoul, Republic of Korea (K.-H.S.); and Bio and Drug Discovery Division, Korea Research Institute of Chemical Technology, Daejeon, Republic of Korea (S.U.C.)
| | - Jie-Young Song
- Division of Radiation Biomedical Research, Korea Institute of Radiological & Medical Sciences, Seoul, Republic of Korea (S.-Y.J., J.-I.P., K.-H.S., J.A., J.K.P., H.-D.U., S.-G.H., J.-Y.S.); Research Center, Pharos I&BT Co., Ltd., Anyang, Republic of Korea (K.-Y.N.); Graduate School of Pharmaceutical Sciences, College of Pharmacy, Ewha Womans University, Seoul, Republic of Korea (K.-H.S.); and Bio and Drug Discovery Division, Korea Research Institute of Chemical Technology, Daejeon, Republic of Korea (S.U.C.)
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Scott SC, Lee SS, Abraham J. Mechanisms of therapeutic CDK4/6 inhibition in breast cancer. Semin Oncol 2019; 44:385-394. [PMID: 29935900 DOI: 10.1053/j.seminoncol.2018.01.006] [Citation(s) in RCA: 40] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/15/2018] [Accepted: 01/21/2018] [Indexed: 12/29/2022]
Abstract
Cyclin dependent kinase (CDK) 4/6 inhibitors have advanced the treatment of metastatic breast cancer by targeting the cell cycle machinery, interrupting intracellular and mitogenic hormone signals that stimulate proliferation of malignant cells. Preclinical evidence demonstrated that derangements of cyclin D1, CDK4/6, and retinoblastoma expression are common in breast cancer, and suggested a therapeutic benefit from interrupting this axis required for cell cycle progression. Studies of cell lines and animal models of breast cancer have demonstrated the complex interplay between the cell cycle and estrogen receptor and human epidermal growth receptor 2 signaling, which informs our understanding of synergistic use of CDK4/6 inhibitors with endocrine therapy, as well as mechanisms of resistance to endocrine therapy. Interestingly, estrogen receptor activity leads to upregulation of cyclin D1 expression, but the estrogen receptor is also in turn activated by cyclin D1, independent of estrogen binding. Early CDK inhibitors were nonspecific and limited by systemic toxicities, while the current generation of CDK4/6 inhibitors have shown promise in the treatment of hormone receptor-positive breast cancer. Preclinical investigations of the three CDK4/6 inhibitors approved by the US Food and Drug Administration (palbociclib, ribociclib, and abemaciclib) lend further insight into their mechanism of action, which will hopefully inform the future use and refinement of these therapies. Finally, we summarize evidence for additional novel CDK4/6 inhibitors currently in development.
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Affiliation(s)
| | - Sarah S Lee
- Cleveland Clinic Taussig Cancer Institute, Cleveland, OH
| | - Jame Abraham
- Cleveland Clinic Taussig Cancer Institute, Cleveland, OH.
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32
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Zhao ZM, Yost SE, Hutchinson KE, Li SM, Yuan YC, Noorbakhsh J, Liu Z, Warden C, Johnson RM, Wu X, Chuang JH, Yuan Y. CCNE1 amplification is associated with poor prognosis in patients with triple negative breast cancer. BMC Cancer 2019; 19:96. [PMID: 30665374 PMCID: PMC6341717 DOI: 10.1186/s12885-019-5290-4] [Citation(s) in RCA: 53] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2018] [Accepted: 01/07/2019] [Indexed: 12/30/2022] Open
Abstract
BACKGROUND Triple negative breast cancer (TNBC) is aggressive with limited treatment options upon recurrence. Molecular discordance between primary and metastatic TNBC has been observed, but the degree of biological heterogeneity has not been fully explored. Furthermore, genomic evolution through treatment is poorly understood. In this study, we aim to characterize the genomic changes between paired primary and metastatic TNBCs through transcriptomic and genomic profiling, and to identify genomic alterations which may contribute to chemotherapy resistance. METHODS Genomic alterations and mRNA expression of 10 paired primary and metastatic TNBCs were determined through targeted sequencing, microarray analysis, and RNA sequencing. Commonly mutated genes, as well as differentially expressed and co-expressed genes were identified. We further explored the clinical relevance of differentially expressed genes between primary and metastatic tumors to patient survival using large public datasets. RESULTS Through gene expression profiling, we observed a shift in TNBC subtype classifications between primary and metastatic TNBCs. A panel of eight cancer driver genes (CCNE1, TPX2, ELF3, FANCL, JAK2, GSK3B, CEP76, and SYK) were differentially expressed in recurrent TNBCs, and were also overexpressed in TCGA and METABRIC. CCNE1 and TPX2 were co-overexpressed in TNBCs. DNA mutation profiling showed that multiple mutations occurred in genes comprising a number of potentially targetable pathways including PI3K/AKT/mTOR, RAS/MAPK, cell cycle, and growth factor receptor signaling, reaffirming the wide heterogeneity of mechanisms driving TNBC. CCNE1 amplification was associated with poor overall survival in patients with metastatic TNBC. CONCLUSIONS CCNE1 amplification may confer resistance to chemotherapy and is associated with poor overall survival in TNBC.
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Affiliation(s)
- Zi-Ming Zhao
- The Jackson Laboratory for Genomic Medicine, Farmington, CT, USA
| | - Susan E Yost
- City of Hope Comprehensive Cancer Center and Beckman Research Institute, 1500 E. Duarte Road, Duarte, CA, 91010, USA
| | | | - Sierra Min Li
- City of Hope Comprehensive Cancer Center and Beckman Research Institute, 1500 E. Duarte Road, Duarte, CA, 91010, USA
| | - Yate-Ching Yuan
- City of Hope Comprehensive Cancer Center and Beckman Research Institute, 1500 E. Duarte Road, Duarte, CA, 91010, USA
| | - Javad Noorbakhsh
- The Jackson Laboratory for Genomic Medicine, Farmington, CT, USA
| | - Zheng Liu
- City of Hope Comprehensive Cancer Center and Beckman Research Institute, 1500 E. Duarte Road, Duarte, CA, 91010, USA
| | - Charles Warden
- City of Hope Comprehensive Cancer Center and Beckman Research Institute, 1500 E. Duarte Road, Duarte, CA, 91010, USA
| | - Radia M Johnson
- Genentech, Inc., Oncology Biomarker Development, South San Francisco, CA, USA
| | - Xiwei Wu
- City of Hope Comprehensive Cancer Center and Beckman Research Institute, 1500 E. Duarte Road, Duarte, CA, 91010, USA
| | - Jeffrey H Chuang
- The Jackson Laboratory for Genomic Medicine, Farmington, CT, USA
| | - Yuan Yuan
- City of Hope Comprehensive Cancer Center and Beckman Research Institute, 1500 E. Duarte Road, Duarte, CA, 91010, USA.
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33
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Roskoski R. Cyclin-dependent protein serine/threonine kinase inhibitors as anticancer drugs. Pharmacol Res 2019; 139:471-488. [DOI: 10.1016/j.phrs.2018.11.035] [Citation(s) in RCA: 157] [Impact Index Per Article: 26.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/26/2018] [Accepted: 11/27/2018] [Indexed: 02/07/2023]
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García-Reyes B, Kretz AL, Ruff JP, von Karstedt S, Hillenbrand A, Knippschild U, Henne-Bruns D, Lemke J. The Emerging Role of Cyclin-Dependent Kinases (CDKs) in Pancreatic Ductal Adenocarcinoma. Int J Mol Sci 2018; 19:E3219. [PMID: 30340359 PMCID: PMC6214075 DOI: 10.3390/ijms19103219] [Citation(s) in RCA: 53] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2018] [Revised: 09/27/2018] [Accepted: 10/11/2018] [Indexed: 02/07/2023] Open
Abstract
The family of cyclin-dependent kinases (CDKs) has critical functions in cell cycle regulation and controlling of transcriptional elongation. Moreover, dysregulated CDKs have been linked to cancer initiation and progression. Pharmacological CDK inhibition has recently emerged as a novel and promising approach in cancer therapy. This idea is of particular interest to combat pancreatic ductal adenocarcinoma (PDAC), a cancer entity with a dismal prognosis which is owed mainly to PDAC's resistance to conventional therapies. Here, we review the current knowledge of CDK biology, its role in cancer and the therapeutic potential to target CDKs as a novel treatment strategy for PDAC.
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Affiliation(s)
- Balbina García-Reyes
- Department of General and Visceral Surgery, Ulm University Hospital, Albert-Einstein-Allee 23, 89081 Ulm, Germany.
| | - Anna-Laura Kretz
- Department of General and Visceral Surgery, Ulm University Hospital, Albert-Einstein-Allee 23, 89081 Ulm, Germany.
| | - Jan-Philipp Ruff
- Department of General and Visceral Surgery, Ulm University Hospital, Albert-Einstein-Allee 23, 89081 Ulm, Germany.
| | - Silvia von Karstedt
- Department of Translational Genomics, University Hospital Cologne, Weyertal 115b, 50931 Cologne, Germany.
- Cologne Excellence Cluster on Cellular Stress Response in Aging-Associated Diseases (CECAD), University of Cologne, Joseph-Stelzmann-Straße 26, 50931 Cologne, Germany.
| | - Andreas Hillenbrand
- Department of General and Visceral Surgery, Ulm University Hospital, Albert-Einstein-Allee 23, 89081 Ulm, Germany.
| | - Uwe Knippschild
- Department of General and Visceral Surgery, Ulm University Hospital, Albert-Einstein-Allee 23, 89081 Ulm, Germany.
| | - Doris Henne-Bruns
- Department of General and Visceral Surgery, Ulm University Hospital, Albert-Einstein-Allee 23, 89081 Ulm, Germany.
| | - Johannes Lemke
- Department of General and Visceral Surgery, Ulm University Hospital, Albert-Einstein-Allee 23, 89081 Ulm, Germany.
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35
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Iqbal NJ, Lu Z, Liu SM, Schwartz GJ, Chua S, Zhu L. Cyclin-dependent kinase 4 is a preclinical target for diet-induced obesity. JCI Insight 2018; 3:123000. [PMID: 30185666 PMCID: PMC6171799 DOI: 10.1172/jci.insight.123000] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2018] [Accepted: 07/26/2018] [Indexed: 12/12/2022] Open
Abstract
When obesity is caused by consumption of a high-fat diet, the tumor suppressor pRb is phosphoinactivated in the neurons of the mediobasal hypothalamus, a brain area critical for energy-balance regulation. However, the functional relevance of pRb phosphoinactivation in the mediobasal hypothalamus to diet-induced obesity remains unknown. Here, we show that inhibiting pRb phosphorylation in the mediobasal hypothalamus can prevent and treat diet-induced obesity in mice. Expressing an unphosphorylable pRb nonselectively in the mediobasal hypothalamus or conditionally in anorexigenic POMC neurons inhibits diet-induced obesity. Intracerebroventricular delivery of US Food and Drug Administration–approved (FDA-approved) cyclin-dependent kinase 4 (CDK4) inhibitor abemaciclib inhibits pRb phosphorylation in the mediobasal hypothalamus and prevents diet-induced obesity. Oral administration of abemaciclib at doses approved for human use reduces fat mass in diet-induced obese mice by increasing lipid oxidation without significantly reducing lean mass. With analysis of recent literature identifying CDK4 as the most abundantly expressed neuronal CDK in the mediobasal hypothalamus, our work uncovers CDK4 as the major kinase for hypothalamic pRb phosphoinactivation and a highly effective central antiobesity target. As three CDK4/6 inhibitors have recently received FDA approval for life-long breast cancer therapy, our study provides a preclinical basis for their expedient repurposing for obesity management. Inhibiting pRb phosphorylation in the mediobasal hypothalamus can prevent and treat diet-induced obesity in mice.
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Affiliation(s)
| | - Zhonglei Lu
- Department of Developmental and Molecular Biology and
| | - Shun Mei Liu
- Department of Medicine, Albert Einstein College of Medicine, New York, New York, USA
| | - Gary J Schwartz
- Department of Medicine, Albert Einstein College of Medicine, New York, New York, USA
| | - Streamson Chua
- Department of Medicine, Albert Einstein College of Medicine, New York, New York, USA
| | - Liang Zhu
- Department of Developmental and Molecular Biology and.,Department of Medicine, Albert Einstein College of Medicine, New York, New York, USA
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Sporikova Z, Koudelakova V, Trojanec R, Hajduch M. Genetic Markers in Triple-Negative Breast Cancer. Clin Breast Cancer 2018; 18:e841-e850. [PMID: 30146351 DOI: 10.1016/j.clbc.2018.07.023] [Citation(s) in RCA: 147] [Impact Index Per Article: 21.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2018] [Revised: 06/22/2018] [Accepted: 07/27/2018] [Indexed: 12/22/2022]
Abstract
Triple-negative breast cancer (TNBC) accounts for 15% to 20% of breast cancer cases and is characterized by the absence of estrogen, progesterone, and human epidermal growth factor 2 receptors. Though TNBC is a highly heterogenic and aggressive disease, TNBC patients have better response to neoadjuvant therapy compared to other breast cancer subtypes. Nevertheless, patients with residual disease have a very poor prognosis, with higher probability of relapse and lower overall survival in the first years after diagnosis. TNBC has 6 subtypes with distinct molecular signatures with different prognoses and probably different responses to therapy. The precise stratification of TNBC is therefore crucial for the development of potent standardized and targeted therapies. In spite of intensive research into finding new molecular biomarkers and designing personalized therapeutic approaches, BRCA mutational status is the only clinically validated biomarker for personalized therapy in TNBC. Recent studies have reported several promising biomarkers that are currently being validated through clinical trials. The objective of this review was to summarize the clinically relevant genetic markers for TNBC that could serve as diagnostic, prognostic, or predictive or could improve personalized therapeutic strategies.
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Affiliation(s)
- Zuzana Sporikova
- Institute of Molecular and Translational Medicine, Faculty of Medicine and Dentistry, Palacky University and University Hospital in Olomouc, Olomouc, Czech Republic
| | - Vladimira Koudelakova
- Institute of Molecular and Translational Medicine, Faculty of Medicine and Dentistry, Palacky University and University Hospital in Olomouc, Olomouc, Czech Republic.
| | - Radek Trojanec
- Institute of Molecular and Translational Medicine, Faculty of Medicine and Dentistry, Palacky University and University Hospital in Olomouc, Olomouc, Czech Republic
| | - Marian Hajduch
- Institute of Molecular and Translational Medicine, Faculty of Medicine and Dentistry, Palacky University and University Hospital in Olomouc, Olomouc, Czech Republic
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37
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Prevo R, Pirovano G, Puliyadi R, Herbert KJ, Rodriguez-Berriguete G, O’Docherty A, Greaves W, McKenna WG, Higgins GS. CDK1 inhibition sensitizes normal cells to DNA damage in a cell cycle dependent manner. Cell Cycle 2018; 17:1513-1523. [PMID: 30045664 PMCID: PMC6132956 DOI: 10.1080/15384101.2018.1491236] [Citation(s) in RCA: 47] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2018] [Revised: 07/01/2018] [Accepted: 06/13/2018] [Indexed: 12/15/2022] Open
Abstract
Cyclin-dependent kinase 1 (CDK1) orchestrates the transition from the G2 phase into mitosis and as cancer cells often display enhanced CDK1 activity, it has been proposed as a tumor specific anti-cancer target. Here we show that the effects of CDK1 inhibition are not restricted to tumor cells but can also reduce viability in non-cancer cells and sensitize them to radiation in a cell cycle dependent manner. Radiosensitization by the specific CDK1 inhibitor, RO-3306, was determined by colony formation assays in three tumor lines (HeLa, T24, SQ20B) and three non-cancer lines (HFL1, MRC-5, RPE). Initial results showed that CDK1 inhibition radiosensitized tumor cells, but did not sensitize normal fibroblasts and epithelial cells in colony formation assays despite effective inhibition of CDK1 signaling. Further investigation showed that normal cells were less sensitive to CDK1 inhibition because they remained predominantly in G1 for a prolonged period when plated in colony formation assays. In contrast, inhibiting CDK1 a day after plating, when the cells were going through G2/M phase, reduced their clonogenic survival both with and without radiation. Our finding that inhibition of CDK1 can damage normal cells in a cell cycle dependent manner indicates that targeting CDK1 in cancer patients may lead to toxicity in normal proliferating cells. Furthermore, our finding that cell cycle progression becomes easily stalled in non-cancer cells under normal culture conditions has general implications for testing anti-cancer agents in these cells.
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Affiliation(s)
- Remko Prevo
- Department of Oncology, Cancer Research UK/MRC Oxford Institute for Radiation Oncology, Gray Laboratories, University of Oxford, Oxford, UK
| | - Giacomo Pirovano
- Department of Oncology, Cancer Research UK/MRC Oxford Institute for Radiation Oncology, Gray Laboratories, University of Oxford, Oxford, UK
| | - Rathi Puliyadi
- Department of Oncology, Cancer Research UK/MRC Oxford Institute for Radiation Oncology, Gray Laboratories, University of Oxford, Oxford, UK
| | - Katharine J. Herbert
- Department of Oncology, Cancer Research UK/MRC Oxford Institute for Radiation Oncology, Gray Laboratories, University of Oxford, Oxford, UK
| | - Gonzalo Rodriguez-Berriguete
- Department of Oncology, Cancer Research UK/MRC Oxford Institute for Radiation Oncology, Gray Laboratories, University of Oxford, Oxford, UK
| | - Alice O’Docherty
- Department of Oncology, Cancer Research UK/MRC Oxford Institute for Radiation Oncology, Gray Laboratories, University of Oxford, Oxford, UK
| | - William Greaves
- Department of Oncology, Cancer Research UK/MRC Oxford Institute for Radiation Oncology, Gray Laboratories, University of Oxford, Oxford, UK
| | - W. Gillies McKenna
- Department of Oncology, Cancer Research UK/MRC Oxford Institute for Radiation Oncology, Gray Laboratories, University of Oxford, Oxford, UK
| | - Geoff S. Higgins
- Department of Oncology, Cancer Research UK/MRC Oxford Institute for Radiation Oncology, Gray Laboratories, University of Oxford, Oxford, UK
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38
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Contreras JI, Robb CM, King HM, Baxter J, Crawford AJ, Kour S, Kizhake S, Sonawane YA, Rana S, Hollingsworth MA, Luo X, Natarajan A. Chemical Genetic Screens Identify Kinase Inhibitor Combinations that Target Anti-Apoptotic Proteins for Cancer Therapy. ACS Chem Biol 2018; 13:1148-1152. [PMID: 29608269 DOI: 10.1021/acschembio.8b00077] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
Abstract
The study presented here provides a framework for the discovery of unique inhibitor combinations that target the apoptosis network for cancer therapy. A pair of doxycycline (Dox)-inducible cell lines that specifically report on the ability of an inhibitor to induce apoptosis by targeting either the Mcl-1 arm or the Bcl-2/Bcl-xL/Bcl-w arm were used. Cell-based assays were optimized for high throughput screening (HTS) with caspase 3/7 as a read out. HTS with a 355-member kinase inhibitor library and the panel of Dox-inducible cell lines revealed that cyclin dependent kinase (CDK) inhibitors induced apoptosis by targeting the Mcl-1 arm, whereas PI3K inhibitors induced apoptosis by targeting the Bcl-2/Bcl-xL/Bcl-w arm. Validation studies identified unique combinations that synergistically inhibited growth and induced apoptosis in a panel of cancer cell lines. Since these inhibitors have been or are currently in clinical trials as single agents, the combinations can be rapidly translated to the clinics.
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39
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Vijayaraghavan S, Moulder S, Keyomarsi K, Layman RM. Inhibiting CDK in Cancer Therapy: Current Evidence and Future Directions. Target Oncol 2017; 13:21-38. [DOI: 10.1007/s11523-017-0541-2] [Citation(s) in RCA: 60] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
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40
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Carey JPW, Karakas C, Bui T, Chen X, Vijayaraghavan S, Zhao Y, Wang J, Mikule K, Litton JK, Hunt KK, Keyomarsi K. Synthetic Lethality of PARP Inhibitors in Combination with MYC Blockade Is Independent of BRCA Status in Triple-Negative Breast Cancer. Cancer Res 2017; 78:742-757. [PMID: 29180466 DOI: 10.1158/0008-5472.can-17-1494] [Citation(s) in RCA: 103] [Impact Index Per Article: 12.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2017] [Revised: 09/29/2017] [Accepted: 11/07/2017] [Indexed: 12/21/2022]
Abstract
PARP inhibitors (PARPi) benefit only a fraction of breast cancer patients. Several of those patients exhibit intrinsic/acquired resistance mechanisms that limit efficacy of PARPi monotherapy. Here we show how the efficacy of PARPi in triple-negative breast cancers (TNBC) can be expanded by targeting MYC-induced oncogenic addiction. In BRCA-mutant/sporadic TNBC patients, amplification of the MYC gene is correlated with increased expression of the homologous DNA recombination enzyme RAD51 and tumors overexpressing both genes are associated with worse overall survival. Combining MYC blockade with PARPi yielded synthetic lethality in MYC-driven TNBC cells. Using the cyclin-dependent kinase inhibitor dinaciclib, which downregulates MYC expression, we found that combination with the PARPi niraparib increased DNA damage and downregulated homologous recombination, leading to subsequent downregulation of the epithelial-mesenchymal transition and cancer stem-like cell phenotypes. Notably, dinaciclib resensitized TBNC cells, which had acquired resistance to niraparib. We found that the synthetic lethal strategy employing dinaciclib and niraparib was also highly efficacious in ovarian, prostate, pancreatic, colon, and lung cancer cells. Taken together, our results show how blunting MYC oncogene addiction can leverage cancer cell sensitivity to PARPi, facilitating the clinical use of c-myc as a predictive biomarker for this treatment.Significance: Dual targeting of MYC-regulated homologous recombination and PARP-mediated DNA repair yields potent synthetic lethality in triple-negative breast tumors and other aggressive tumors characterized by MYC overexpression. Cancer Res; 78(3); 742-57. ©2017 AACR.
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Affiliation(s)
- Jason P W Carey
- Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
| | - Cansu Karakas
- Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Tuyen Bui
- Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Xian Chen
- Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Smruthi Vijayaraghavan
- Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Yang Zhao
- Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Jing Wang
- Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Keith Mikule
- Tesaro Biopharmaceuticals, Waltham, Massacheusetts
| | - Jennifer K Litton
- Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Kelly K Hunt
- Department of Breast Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Khandan Keyomarsi
- Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
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Hematological adverse effects in breast cancer patients treated with cyclin-dependent kinase 4 and 6 inhibitors: a systematic review and meta-analysis. Breast Cancer 2017; 25:17-27. [DOI: 10.1007/s12282-017-0818-4] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2017] [Accepted: 11/12/2017] [Indexed: 10/18/2022]
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42
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Alexander A, Karakas C, Chen X, Carey JPW, Yi M, Bondy M, Thompson P, Cheung KL, Ellis IO, Gong Y, Krishnamurthy S, Alvarez RH, Ueno NT, Hunt KK, Keyomarsi K. Cyclin E overexpression as a biomarker for combination treatment strategies in inflammatory breast cancer. Oncotarget 2017; 8:14897-14911. [PMID: 28107181 PMCID: PMC5362453 DOI: 10.18632/oncotarget.14689] [Citation(s) in RCA: 35] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2016] [Accepted: 12/26/2016] [Indexed: 12/18/2022] Open
Abstract
Inflammatory breast cancer (IBC) is a virulent form of breast cancer, and novel treatment strategies are urgently needed. Immunohistochemical analysis of tumors from women with a clinical diagnosis of IBC (n = 147) and those with non-IBC breast cancer (n = 2510) revealed that, whereas in non-IBC cases cytoplasmic cyclin E was highly correlated with poor prognosis (P < 0.001), in IBC cases both nuclear and cytoplasmic cyclin E were indicative of poor prognosis. These results underscored the utility of the cyclin E/CDK2 complex as a novel target for treatment. Because IBC cell lines were highly sensitive to the CDK2 inhibitors dinaciclib and meriolin 5, we developed a high-throughput survival assay (HTSA) to design novel sequential combination strategies based on the presence of cyclin E and CDK2. Using a 14-cell-line panel, we found that dinaciclib potentiated the activity of DNA-damaging chemotherapies treated in a sequence of dinaciclib followed by chemotherapy, whereas this was not true for paclitaxel. We also identified a signature of DNA repair–related genes that are downregulated by dinaciclib, suggesting that global DNA repair is inhibited and that prolonged DNA damage leads to apoptosis. Taken together, our findings argue that CDK2-targeted combinations may be viable strategies in IBC worthy of future clinical investigation.
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Affiliation(s)
- Angela Alexander
- Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.,Morgan Welch Inflammatory Breast Cancer Research Program and Clinic, Houston, Texas, USA
| | - Cansu Karakas
- Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Xian Chen
- Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Jason P W Carey
- Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Min Yi
- Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Melissa Bondy
- Department of Pediatrics, Baylor College of Medicine, Houston, Texas, USA
| | - Patricia Thompson
- Department of Pathology, Stony Brook School of Medicine, Stony Brook, New York, USA
| | | | - Ian O Ellis
- University of Nottingham, School of Medicine, Nottingham, UK
| | - Yun Gong
- Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Savitri Krishnamurthy
- Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.,Morgan Welch Inflammatory Breast Cancer Research Program and Clinic, Houston, Texas, USA
| | - Ricardo H Alvarez
- Morgan Welch Inflammatory Breast Cancer Research Program and Clinic, Houston, Texas, USA.,Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Naoto T Ueno
- Morgan Welch Inflammatory Breast Cancer Research Program and Clinic, Houston, Texas, USA.,Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Kelly K Hunt
- Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Khandan Keyomarsi
- Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
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43
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Jia H, Truica CI, Wang B, Wang Y, Ren X, Harvey HA, Song J, Yang JM. Immunotherapy for triple-negative breast cancer: Existing challenges and exciting prospects. Drug Resist Updat 2017; 32:1-15. [PMID: 29145974 DOI: 10.1016/j.drup.2017.07.002] [Citation(s) in RCA: 132] [Impact Index Per Article: 16.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2017] [Revised: 07/17/2017] [Accepted: 07/20/2017] [Indexed: 12/21/2022]
Abstract
Patients with breast tumors that do not express the estrogen receptor, the progesterone receptor, nor Her-2/neu are hence termed "triple negatives", and generally have a poor prognosis, with high rates of systemic recurrence and refractoriness to conventional therapy regardless of the choice of adjuvant treatment. Thus, more effective therapeutic options are sorely needed for triple-negative breast cancer (TNBC), which occurs in approximately 20% of diagnosed breast cancers. In recent years, exploiting intrinsic mechanisms of the host immune system to eradicate cancer cells has achieved impressive success, and the advances in immunotherapy have yielded potential new therapeutic strategies for the treatment of this devastating subtype of breast cancer. It is anticipated that the responses initiated by immunotherapeutic interventions will explicitly target and annihilate tumor cells, while at the same time spare normal cells. Various immunotherapeutic approaches have been already developed and tested, which include the blockade of immune checkpoints using neutralizing or blocking antibodies, induction of cytotoxic T lymphocytes (CTLs), adoptive cell transfer-based therapy, and modulation of the tumor microenvironment to enhance the activity of CTLs. One of the most important areas of breast cancer research today is understanding the immune features and profiles of TNBC and devising novel immune-modulatory strategies to tackling TNBC, a subtype of breast cancer notorious for its poor prognosis and its imperviousness to conventional treatments. On the optimal side, one can anticipate that novel, effective, and personalized immunotherapy for TNBC will soon achieve more success and impact clinical treatment of this disease which afflicts approximately 20% of patients with breast cancer. In the present review, we highlight the current progress and encouraging developments in cancer immunotherapy, with a goal to discuss the challenges and to provide future perspectives on how to exploit a variety of new immunotherapeutic approaches including checkpoint inhibitors and neoadjuvant immunotherapy for the treatment of patients with TNBC.
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Affiliation(s)
- Hongyan Jia
- Department of General Surgery, First Hospital of Shanxi Medical University, Taiyuan, Shanxi, 03001, China.
| | - Cristina I Truica
- Department of Medicine, The Penn State Cancer Institute, The Pennsylvania State University College of Medicine, Hershey, PA 17033, USA
| | - Bin Wang
- Department of General Surgery, First Hospital of Shanxi Medical University, Taiyuan, Shanxi, 03001, China
| | - Yanhong Wang
- Department of Microbiology and Immunology, Shanxi Medical University, Taiyuan, Shanxi, 03001, China
| | - Xingcong Ren
- Department of Pharmacology, The Penn State Cancer Institute, The Pennsylvania State University College of Medicine, Hershey, PA 17033, USA
| | - Harold A Harvey
- Department of Medicine, The Penn State Cancer Institute, The Pennsylvania State University College of Medicine, Hershey, PA 17033, USA
| | - Jianxun Song
- Department of Microbiology and Immunology, The Penn State Cancer Institute, The Pennsylvania State University College of Medicine, Hershey, PA 17033, USA
| | - Jin-Ming Yang
- Department of Pharmacology, The Penn State Cancer Institute, The Pennsylvania State University College of Medicine, Hershey, PA 17033, USA.
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Inhibition of Cdk5 induces cell death of tumor-initiating cells. Br J Cancer 2017; 116:912-922. [PMID: 28222068 PMCID: PMC5379151 DOI: 10.1038/bjc.2017.39] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2017] [Revised: 01/23/2017] [Accepted: 01/26/2017] [Indexed: 12/20/2022] Open
Abstract
Background: Tumour-initiating cells (TICs) account for chemoresistance, tumour recurrence and metastasis, and therefore represent a major problem in tumour therapy. However, strategies to address TICs are limited. Recent studies indicate Cdk5 as a promising target for anti-cancer therapy and Cdk5 has recently been associated with epithelial–mesenchymal transition (EMT). However, a role of Cdk5 in TICs has not been described yet. Methods: Expression of Cdk5 in human cancer tissue was analysed by staining of a human tissue microarray (TMA). Functional effects of Cdk5 overexpression, genetic knockdown by siRNA and shRNA, and pharmacologic inhibition by the small molecule roscovitine were tested in migration, invasion, cell death, and tumorsphere assays and in tumour establishment in vivo. For mechanistic studies, molecular biology methods were applied. Results: In fact, here we pin down a novel function of Cdk5 in TICs: knockdown and pharmacological inhibition of Cdk5 impaired tumorsphere formation and reduced tumour establishment in vivo. Conversely, Cdk5 overexpression promoted tumorsphere formation which was in line with increased expression of Cdk5 in human breast cancer tissues as shown by staining of a human TMA. In order to understand how Cdk5 inhibition affects tumorsphere formation, we identify a role of Cdk5 in detachment-induced cell death: Cdk5 inhibition induced apoptosis in tumorspheres by stabilizing the transcription factor Foxo1 which results in increased levels of the pro-apoptotic protein Bim. Conclusions: In summary, our study elucidates a Cdk5-Foxo1-Bim pathway in cell death in tumorspheres and suggests Cdk5 as a potential target to address TICs.
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Cai Z, Liu Q. Cell Cycle Regulation in Treatment of Breast Cancer. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2017; 1026:251-270. [PMID: 29282688 DOI: 10.1007/978-981-10-6020-5_12] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
Cell cycle progression and cell proliferation are under precise and orchestrated control in normal cells. However, uncontrolled cell proliferation caused by aberrant cell cycle progression is a crucial characteristic of cancer. Understanding cell cycle progression and its regulation sheds light on cancer treatment. Agents targeting cell cycle regulators (such as CDKs) have been considered as promising candidates in cancer treatment. Although the first-generation pan-CDK inhibitors failed in clinical trials because of their adverse events and low efficacy, new selective CDK 4/6 inhibitors showed potent efficacy with tolerable safety in preclinical and clinical studies. Here we will review the mechanisms of cell cycle regulation and targeting key cell cycle regulators (such as CDKs) in breast cancer treatment. Particularly, we will discuss the mechanism of CDK inhibitors in disrupting cell cycle progression, the use of selective CDK4/6 inhibitors in treatment of advanced, hormone receptor (HR)-positive postmenopausal breast cancer patients, and other clinical trials that aim to extend the utilization of these agents.
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Affiliation(s)
- Zijie Cai
- Breast Tumor Center, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, 107 Yanjiang West Road, Guangzhou, 510120, Guangdong, China
| | - Qiang Liu
- Breast Tumor Center, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, 107 Yanjiang West Road, Guangzhou, 510120, Guangdong, China.
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Costa R, Carneiro B, Wainwright D, Santa-Maria C, Kumthekar P, Chae Y, Gradishar W, Cristofanilli M, Giles F. Developmental therapeutics for patients with breast cancer and central nervous system metastasis: current landscape and future perspectives. Ann Oncol 2017; 28:44-56. [PMID: 28177431 PMCID: PMC7360139 DOI: 10.1093/annonc/mdw532] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Abstract
Breast cancer is the second-leading cause of metastatic disease in the central nervous system (CNS). Recent advances in the biological understanding of breast cancer have facilitated an unprecedented increase of survival in a subset of patients presenting with metastatic breast cancer. Patients with HER2 positive (HER2+) or triple negative breast cancer are at highest risk of developing CNS metastasis, and typically experience a poor prognosis despite treatment with local and systemic therapies. Among the obstacles ahead in the realm of developmental therapeutics for breast cancer CNS metastasis is the improvement of our knowledge on its biological nuances and on the interaction of the blood–brain barrier with new compounds. This article reviews recent discoveries related to the underlying biology of breast cancer brain metastases, clinical progress to date and suggests rational approaches for investigational therapies.
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Affiliation(s)
- R. Costa
- Developmental Therapeutics Program, Feinberg School of Medicine and Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago
| | - B.A. Carneiro
- Developmental Therapeutics Program, Feinberg School of Medicine and Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago
| | - D.A. Wainwright
- Department of Pathology
- Department of Neurology
- Department of Microbiology-Immunology, Feinberg School of Medicine, Northwestern University, Chicago, USA
| | - C.A. Santa-Maria
- Developmental Therapeutics Program, Feinberg School of Medicine and Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago
| | | | - Y.K. Chae
- Developmental Therapeutics Program, Feinberg School of Medicine and Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago
| | - W.J. Gradishar
- Developmental Therapeutics Program, Feinberg School of Medicine and Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago
| | - M. Cristofanilli
- Developmental Therapeutics Program, Feinberg School of Medicine and Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago
| | - F.J. Giles
- Developmental Therapeutics Program, Feinberg School of Medicine and Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago
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Hu H, Wu J, Ao M, Wang H, Zhou T, Xue Y, Qiu Y, Fang M, Wu Z. Synthesis, structure-activity relationship studies and biological evaluation of novel 2,5-disubstituted indole derivatives as anticancer agents. Chem Biol Drug Des 2016; 88:766-778. [PMID: 27315790 DOI: 10.1111/cbdd.12808] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2016] [Revised: 06/05/2016] [Accepted: 06/12/2016] [Indexed: 01/13/2023]
Abstract
Three novel series of 2,5-disubstituted indole derivatives were synthesized and evaluated in vitro for their antiproliferative activity against human cancer cells and HIV-1 inhibition activity used as a readout of cellular activity. Most compounds were found to have potent anticancer activity. In particular, 2c and 3b which showed effectively to repress HIV-1 transcription had a pan antiproliferative activity in cervical cancer cells (HeLa), breast cancer cells (MCF-7), liver cancer cells (HepG2), and lung cancer cells (H460 and A549). While 3b exhibited high sensitivity to A549 cells with the IC50 value 0.48 ± 0.15 μm, 2c showed high selectivity toward HepG2 cells with the IC50 value 13.21 ± 0.30 μm. With respect to the cellular mechanism of action, HepG2 cells treated with 2c and A549 cells treated with 3b for 24 h were studied by annexin V/PI staining and Western blot analysis, and results revealed that 2c and 3b may induce cancer cells apoptosis through inhibiting the phosphorylation at Ser2 of RNAPII CTD which can be phosphorylated by cyclin-dependent kinase 9. These studies indicated that 2c and 3b may develop as potent lead compounds in the therapy of cancer. However, determining their roles in preventing HIV-1 still requires further intensive study.
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Affiliation(s)
- Hongyu Hu
- School of Pharmaceutical Sciences and the Key Laboratory for Chemical Biology of Fujian Province, Xiamen University, Xiamen, China
| | - Jun Wu
- School of Pharmaceutical Sciences and the Key Laboratory for Chemical Biology of Fujian Province, Xiamen University, Xiamen, China
| | - Mingtao Ao
- School of Pharmaceutical Sciences and the Key Laboratory for Chemical Biology of Fujian Province, Xiamen University, Xiamen, China
| | - Huiru Wang
- School of Pharmaceutical Sciences and the Key Laboratory for Chemical Biology of Fujian Province, Xiamen University, Xiamen, China
| | - Tongtong Zhou
- School of Pharmaceutical Sciences and the Key Laboratory for Chemical Biology of Fujian Province, Xiamen University, Xiamen, China
| | - Yuhua Xue
- School of Pharmaceutical Sciences and the Key Laboratory for Chemical Biology of Fujian Province, Xiamen University, Xiamen, China
| | - Yingkun Qiu
- School of Pharmaceutical Sciences and the Key Laboratory for Chemical Biology of Fujian Province, Xiamen University, Xiamen, China
| | - Meijuan Fang
- School of Pharmaceutical Sciences and the Key Laboratory for Chemical Biology of Fujian Province, Xiamen University, Xiamen, China.
| | - Zhen Wu
- School of Pharmaceutical Sciences and the Key Laboratory for Chemical Biology of Fujian Province, Xiamen University, Xiamen, China.
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48
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Roskoski R. Cyclin-dependent protein kinase inhibitors including palbociclib as anticancer drugs. Pharmacol Res 2016; 107:249-275. [DOI: 10.1016/j.phrs.2016.03.012] [Citation(s) in RCA: 138] [Impact Index Per Article: 15.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/10/2016] [Accepted: 03/11/2016] [Indexed: 02/07/2023]
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Head-to-head comparison of the impact of Aurora A, Aurora B, Repp86, CDK1, CDK2 and Ki67 expression in two of the most relevant gynaecological tumor entities. Arch Gynecol Obstet 2016; 294:813-23. [PMID: 27101368 DOI: 10.1007/s00404-016-4104-z] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2016] [Accepted: 04/08/2016] [Indexed: 12/25/2022]
Abstract
PURPOSE The dysregulation of cell cycle kinases plays a crucial role in carcinogenesis and the expression of various kinases has been attributed to aggressive tumor growth and an unfavourable prognosis in oncological patients. We, therefore, aimed to evaluate the expression of Ki67 among five additional cell cycle kinases in a collective of mammary and ovarian tumor specimens and to find a correlation with clinicopathological parameters. METHODS 76 mammary and 93 ovarian benign and malignant tumor samples were immunohistochemically stained and evaluated for the expression of Aurora A and B, Repp86, CDK1 and 2 (only breast specimens) and Ki67. The expression patterns of these cell cycle kinases were matched with retrospectively collected clinicopathological parameters. RESULTS All examined cell cycle kinases accurately discriminated benign from malignant breast and ovarian tissues. In breast cancer, Aurora A and B-, Repp86-, CDK2- and Ki67-expression was inversely associated with ER expression. No correlation with the HER2-status was found in our collective. Importantly, we found a significant correlation between the expression of Aurora A and CDK1 and axillary lymph node metastasis in breast cancer. Furthermore, a shortened disease free survival (DFS) upon expression of Aurora B and CDK2 was shown in breast cancer patients. None of the cell cycle kinases was associated with predictive or prognostic factors in epithelial ovarian cancer. CONCLUSION The prognostic value of the expression of Ki67 is overtrumped by alternative cell cycle kinases when it comes to prediction of axillary tumor spread and a shortened DFS, which might allow a further risk stratification in breast cancer patients.
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Balakrishnan A, Vyas A, Deshpande K, Vyas D. Pharmacological cyclin dependent kinase inhibitors: Implications for colorectal cancer. World J Gastroenterol 2016; 22:2159-2164. [PMID: 26900281 PMCID: PMC4734993 DOI: 10.3748/wjg.v22.i7.2159] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/21/2015] [Revised: 12/04/2015] [Accepted: 12/30/2015] [Indexed: 02/06/2023] Open
Abstract
Colorectal cancer accounts for a significant proportion of cancer deaths worldwide. The need to develop more chemotherapeutic agents to combat this disease is critical. Cyclin dependent kinases (CDKs), along with its binding partner cyclins, serve to control the growth of cells through the cell cycle. A new class of drugs, termed CDK inhibitors, has been studied in preclinical and now clinical trials. These inhibitors are believed to act as an anti-cancer drug by blocking CDKs to block the uncontrolled cellular proliferation that is hallmark of cancers like colorectal cancer. CDK article provides overview of the emerging drug class of CDK inhibitors and provides a list of ones that are currently in clinical trials.
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