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Cdk4 inhibitor

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https://www.readbyqxmd.com/read/29156680/vemurafenib-resistance-via-de-novo-rbm-genes-mutations-and-chromosome-5-aberrations-is-overcome-by-combined-therapy-with-palbociclib-in-thyroid-carcinoma-with-braf-v600e
#1
Zeus A Antonello, Nancy Hsu, Manoj Bhasin, Giovanni Roti, Mukta Joshi, Paul Van Hummelen, Emily Ye, Agnes S Lo, S Ananth Karumanchi, Christine R Bryke, Carmelo Nucera
Purpose: Papillary thyroid carcinoma (PTC) is the most frequent endocrine tumor. BRAF(V600E) represents the PTC hallmark and is targeted with selective inhibitors (e.g. vemurafenib). Although there have been promising results in clinical trials using these inhibitors, most patients develop resistance and progress. Tumor clonal diversity is proposed as one mechanism underlying drug resistance. Here we have investigated mechanisms of primary and secondary resistance to vemurafenib in BRAF(WT/V600E)-positive PTC patient-derived cells with P16(-/-) (CDKN2A(-/-))...
October 17, 2017: Oncotarget
https://www.readbyqxmd.com/read/29153893/selective-atp-competitive-leads-of-cdk4-discovery-by-3d-qsar-pharmacophore-mapping-and-molecular-docking-approach
#2
Rohini Rondla, Lavanya Souda PadmaRao, Vishwanath Ramatenki, Aboubakr Haredi-Abdel-Monsef, Sarita Rajender Potlapally, Uma Vuruputuri
The discovery of ATP competitive CDK4 inhibitors is an on-going challenging task in cancer therapy. Here, an attempt has been made to develop new leads targeting ATP binding site of CDK4 by applying 3D-QSAR pharmacophore mapping and molecular docking methods The outcome of 6 leads offers a significant contribution for selective CDK4 inhibition, since they show potential binding interactions with Val(96), Arg(101), and Glu(144) residues of CDK4, that are unique and from other kinases. It is worth noting that there is a striking similarity in binding interactions of the leads and known CDK4 inhibitors, namely Abemaciclib, Palbociclib and Ribociclib...
November 14, 2017: Computational Biology and Chemistry
https://www.readbyqxmd.com/read/29152059/gzd824-suppresses-the-growth-of-human-b-cell-precursor-acute-lymphoblastic-leukemia-cells-by-inhibiting-the-src-kinase-and-pi3k-akt-pathways
#3
Wei Ye, Zhiwu Jiang, Xiaoyun Lu, Xiaomei Ren, Manman Deng, Shouheng Lin, Yiren Xiao, Simiao Lin, Suna Wang, Baiheng Li, Yi Zheng, Peilong Lai, Jianyu Weng, Donghai Wu, Yuguo Ma, Xudong Chen, Zhesheng Wen, Yaoyu Chen, Xiaoyan Feng, Yangqiu Li, Pentao Liu, Xin Du, Duanqing Pei, Yao Yao, Bing Xu, Ke Ding, Peng Li
Available therapeutic options for advanced B cell precursor acute lymphoblastic leukemia (pre-B ALL) are limited. Many lead to neutropenia, leaving patients at risk of life-threatening infections and result in bad outcomes. New treatment options are needed to improve overall survival. We previously showed that GZD824, a novel BCR-ABL tyrosine kinase inhibitor, has anti-tumor activity in Philadelphia chromosome-positive (Ph+) chronic myeloid leukemia cells and tumor models. Here, we show that GZD824 decreases cell viability, induces cell-cycle arrest, and causes apoptosis in pre-B ALL cells...
October 20, 2017: Oncotarget
https://www.readbyqxmd.com/read/29150788/ck4-ck6-cyclin-d1-p16-ink4a-and-egfr-expression-in-glioblastoma-with-a-primitive-neuronal-component
#4
Guiyan Xu, Jian Yi Li
Glioblastoma with primitive neuroectodermal tumor-like component (GBM-PNET) is a rare variant of glioblastoma, which was renamed as glioblastoma with a primitive neuronal component (GBM-PN) in new WHO classification of tumours of the central nervous system in 2016. There are few publications on the investigation of GBM-PN. In this study, PCR mRNA arrays on 6 cases of conventional GBM and 10 cases of GBM-PN showed high mRNA level of CDK4 in GBM-PN and low mRNA level of EGFR in GBM-PN. Immunohistochemical stains on tissue microarrays with 28 cases of conventional GBM and 13 cases of GBM-PN demonstrated that CDK4 was selectively expressed in the primitive neuronal component of all GBM-PN cases while EGFR was positive in conventional GBM and glial component of GBM-PN, but was negative in the primitive neuronal component of all GBM-PN cases...
November 17, 2017: Journal of Neuro-oncology
https://www.readbyqxmd.com/read/29147869/hematological-adverse-effects-in-breast-cancer-patients-treated-with-cyclin-dependent-kinase-4-and-6-inhibitors-a-systematic-review-and-meta-analysis
#5
REVIEW
Loay Kassem, Kyrillus S Shohdy, Shaimaa Lasheen, Omar Abdel-Rahman, Thomas Bachelot
BACKGROUND: The introduction of specific cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors significantly improved progression-free survival in hormone receptor-positive metastatic breast cancer. CDK 4/6 inhibitors induce cell cycle arrest via liberating the tumor suppressor retinoblastoma protein from CDK4/6 inhibitory effect. Preliminary studies suggested an increase in the hematological toxicities which might affect the quality of life in such palliative setting. METHODS: We searched PubMed, ASCO, ESMO and San Antonio meeting databases for randomized phase II/III trials in metastatic breast cancer receiving CDK4/6 inhibitors with safety data provided on the incidence of hematological adverse effects...
November 16, 2017: Breast Cancer: the Journal of the Japanese Breast Cancer Society
https://www.readbyqxmd.com/read/29146887/targeted-therapy-of-gastroenteropancreatic-neuroendocrine-tumours-preclinical-strategies-and-future-targets
#6
Elke Tatjana Aristizabal Prada, Christoph J Auernhammer
Molecular targeted therapy of advanced neuroendocrine tumours (NETs) of the gastroenteropancreatic (GEP) system currently encompasses approved therapy with the mTOR-inhibitor everolimus and the multi-tyrosinkinase inhibitor sunitinib. However clinical efficacy of these treatment strategies is limited by low objective response rates and limited progression free survival due to tumor resistance. Further novel strategies for molecular targeted therapy of NETs of the GEP-system are needed. This paper reviews preclinical research models and signaling pathways in NETs of the GEP-system...
November 16, 2017: Endocrine Connections
https://www.readbyqxmd.com/read/29137354/erps294-is-a-biomarker-of-ligand-or-mutational-er%C3%AE-activation-and-a-breast-cancer-target-for-cdk2-inhibition
#7
Gary K Scott, David Chu, Ravneet Kaur, Julia Malato, Daniel E Rothschild, Katya Frazier, Serenella Eppenberger-Castori, Byron Hann, Ben Ho Park, Christopher C Benz
ERα phosphorylation at hinge site S294 (pS294) was recently shown to be essential for ER-dependent gene transcription and mediated by an unknown cyclin-dependent kinase (CDK). This study was undertaken to identify the exact CDK pathway mediating pS294 formation, and to determine if this phosphorylation event occurs with, and can be targeted to treat, the ligand-independent growth of breast cancers expressing endocrine-refractory ESR1 mutations. Using a newly developed anti-pS294 monoclonal antibody, a combination of CDK specific siRNA knockdown studies and a broad panel of CDK selective inhibitors against ligand (E2)-stimulated MCF7 cells, we first identified CDK2 as the primary mediator of pS294 formation and showed that CDK2-selective inhibitors like Dinaciclib, but not CDK4/6 inhibitors like Palbociclib, can selectively prevent pS294 formation and repress ER-dependent gene expression...
October 13, 2017: Oncotarget
https://www.readbyqxmd.com/read/29137335/inhibition-of-cell-cycle-progression-by-the-hydroxytyrosol-cetuximab-combination-yields-enhanced-chemotherapeutic-efficacy-in-colon-cancer-cells
#8
Erika Terzuoli, Ginevra Nannelli, Maria Frosini, Antonio Giachetti, Marina Ziche, Sandra Donnini
Hydroxytyrosol (HT), a polyphenol of olive oil, downregulates epidermal growth factor (EGFR) expression and inhibits cell proliferation in colon cancer (CC) cells, with mechanisms similar to that activated by the EGFR inhibitor, cetuximab. Here, we studied whether HT treatment would enhance the cetuximab inhibitory effects on cell growth in CC cells. HT-cetuximab combination showed greater efficacy in reducing cell growth in HT-29 and WiDr cells at concentrations 10 times lower than when used as single agents...
October 10, 2017: Oncotarget
https://www.readbyqxmd.com/read/29134609/expression-of-p27-kip1-and-p18-ink4c-in-human-multiple-endocrine-neoplasia-type-1-related-pancreatic-neuroendocrine-tumors
#9
E B Conemans, G M Raicu-Ionita, C R C Pieterman, K M A Dreijerink, O M Dekkers, A R Hermus, W W de Herder, M L Drent, A N A van der Horst-Schrivers, B Havekes, P H Bisschop, G J Offerhaus, I H M Borel Rinkes, G D Valk, H Th M Timmers, M R Vriens
PURPOSE: Pancreatic neuroendocrine tumors are a major manifestation of multiple endocrine neoplasia type 1 (MEN1). This tumor syndrome is caused by germline mutations in MEN1, encoding menin. Insight into pathogenesis of these tumors might lead to new biomarkers and therapeutic targets for these patients. Several lines of evidence point towards a role for p27(Kip1) and p18(Ink4c) in MEN1-related tumor development in animal models for MEN1, but their contribution to human MEN1-related pancreatic neuroendocrine tumor development is not known...
November 13, 2017: Journal of Endocrinological Investigation
https://www.readbyqxmd.com/read/29133594/competitive-kinase-enrichment-proteomics-reveals-that-abemaciclib-inhibits-gsk3%C3%AE-and-activates-wnt-signaling
#10
Emily M Cousins, Dennis Goldfarb, Feng Yan, Jose Roques, David B Darr, Gary L Johnson, Michael B Major
The cellular and organismal phenotypic response to a small-molecule kinase inhibitor is defined collectively by the inhibitor's targets and their functions. The selectivity of small-molecule kinase inhibitors is commonly determined in vitro, using purified kinases and substrates. Recently, competitive chemical proteomics has emerged as a complementary, unbiased, cell-based methodology to define the target landscape of kinase inhibitors. Here, we evaluated and optimized a competitive multiplexed inhibitor bead mass spectrometry (MIB/MS) platform using cell lysates, live cells, and treated mice...
November 13, 2017: Molecular Cancer Research: MCR
https://www.readbyqxmd.com/read/29133590/genotoxic-damage-activates-the-ampk-%C3%AE-1-isoform-in-the-nucleus-via-ca2-camkk2-signaling-to-enhance-tumor-cell-survival
#11
Diana Vara Ciruelos, Madhumita Dandapani, Alexander Gray, Ejaife O Egbani, A Mark Evans, D Grahame Hardie
Many genotoxic cancer treatments activate AMP-activated protein kinase (AMPK), but the mechanisms of AMPK activation in response to DNA damage, and its downstream consequences, have been unclear. In this study, etoposide activates the α1 but not the α2 isoform of AMPK, primarily within the nucleus. AMPK activation is independent of ataxia-telangiectasia mutated (ATM), a DNA damage-activated kinase, and the principal upstream kinase for AMPK, LKB1, but correlates with increased nuclear Ca2+ and requires the Ca2+/calmodulin-dependent kinase, CaMKK2...
November 13, 2017: Molecular Cancer Research: MCR
https://www.readbyqxmd.com/read/29131001/atorvastatin-calcium-inhibits-pdgf-%C3%AE-%C3%AE-induced-proliferation-and-migration-of-vsmcs-through-the-g0-g1-cell-cycle-arrest-and-suppression-of-activated-pdgfr%C3%AE-pi3k-akt-signaling-cascade
#12
Shuang Chen, Siyuan Dong, Zhao Li, Xiaofan Guo, Naijin Zhang, Bo Yu, Yingxian Sun
BACKGROUND/AIMS: Abnormal proliferation of vascular smooth muscle cells (VSMCs) is a hallmark of vascular lesions, such as atherosclerosis and restenosis. PDGF-ββ, an isoform of PDGF (platelet-derived growth factor), has been demonstrated to induce proliferation and migration of VSMCs. Atorvastatin calcium, a selective inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, has favorable protective effects on VSMCs. This study examined the effects of atorvastatin calcium on the proliferation and migration of PDGF-ββ-treated VSMCs, as well as its underlying mechanisms...
November 9, 2017: Cellular Physiology and Biochemistry
https://www.readbyqxmd.com/read/29113274/simvastatin-potentiates-doxorubicin-activity-against-mcf-7-breast-cancer-cells
#13
Benjaporn Buranrat, Wanwisa Suwannaloet, Jarinyaporn Naowaboot
Simvastatin is a low density lipoprotein-lowering drug that is widely used to prevent and treat cardiovascular disease by inhibiting the mevalonate pathway. Simvastatin also exhibits inhibitory effects on a number of types of cancer. In the present study, the effects of simvastatin on the activity of doxorubicin in the breast cancer MCF-7 cell line, and the mechanisms by which this interaction occurs were investigated. The effect of simvastatin and doxorubicin treatment, alone and in combination, on the growth of MCF-7 cells was evaluated by a sulforhodamine B and colony formation assay...
November 2017: Oncology Letters
https://www.readbyqxmd.com/read/29112787/dabrafenib-inhibits-the-growth-of-braf-wt-cancers-through-cdk16-and-nek9-inhibition
#14
Manali Phadke, Lily L Remsing Rix, Inna Smalley, Annamarie T Bryant, Yunting Luo, Harshani R Lawrence, Braydon J Schaible, Y Ann Chen, Uwe Rix, Keiran S M Smalley
Although the BRAF inhibitors dabrafenib and vemurafenib have both proven successful against BRAF-mutant melanoma, there seem to be differences in their mechanisms of action. Here, we show that dabrafenib is more effective at inhibiting the growth of NRAS-mutant and KRAS-mutant cancer cell lines than vemurafenib. Using mass spectrometry-based chemical proteomics we identified NEK9 and CDK16 as unique targets of dabrafenib. Both NEK9 and CDK16 were highly expressed in specimens of advanced melanoma, with high expression of both proteins correlating with a worse overall survival...
November 7, 2017: Molecular Oncology
https://www.readbyqxmd.com/read/29108713/risk-of-adverse-events-with-the-addition-of-targeted-agents-to-endocrine-therapy-in-patients-with-hormone-receptor-positive-metastatic-breast-cancer-a-systematic-review-and-meta-analysis
#15
REVIEW
Samuel Martel, Marco Bruzzone, Marcello Ceppi, Christian Maurer, Noam Falbel Ponde, Arlindo R Ferreira, Giulia Viglietti, Lucia Del Mastro, Catherine Prady, Evandro de Azambuja, Matteo Lambertini
BACKGROUND: Combining targeted agents and endocrine therapy (ET) improves outcomes in hormone receptor-positive metastatic breast cancer patients but increases the risk of adverse events (AEs). This meta-analysis aims to estimate the comparative risk of AEs with ET in addition to targeted agents in this setting. METHODS: A systematic literature search of MEDLINE, EMBASE, Cochrane Library and conference proceedings up to July 17th 2017 was conducted to identify randomized controlled trials investigating ET with or without CDK4/6, mTOR, PI3K inhibitors and anti-HER2 agents...
October 28, 2017: Cancer Treatment Reviews
https://www.readbyqxmd.com/read/29106415/evolution-and-clinical-impact-of-co-occurring-genetic-alterations-in-advanced-stage-egfr-mutant-lung-cancers
#16
Collin M Blakely, Thomas B K Watkins, Wei Wu, Beatrice Gini, Jacob J Chabon, Caroline E McCoach, Nicholas McGranahan, Gareth A Wilson, Nicolai J Birkbak, Victor R Olivas, Julia Rotow, Ashley Maynard, Victoria Wang, Matthew A Gubens, Kimberly C Banks, Richard B Lanman, Aleah F Caulin, John St John, Anibal R Cordero, Petros Giannikopoulos, Andrew D Simmons, Philip C Mack, David R Gandara, Hatim Husain, Robert C Doebele, Jonathan W Riess, Maximilian Diehn, Charles Swanton, Trever G Bivona
A widespread approach to modern cancer therapy is to identify a single oncogenic driver gene and target its mutant-protein product (for example, EGFR-inhibitor treatment in EGFR-mutant lung cancers). However, genetically driven resistance to targeted therapy limits patient survival. Through genomic analysis of 1,122 EGFR-mutant lung cancer cell-free DNA samples and whole-exome analysis of seven longitudinally collected tumor samples from a patient with EGFR-mutant lung cancer, we identified critical co-occurring oncogenic events present in most advanced-stage EGFR-mutant lung cancers...
November 6, 2017: Nature Genetics
https://www.readbyqxmd.com/read/29103955/cell-cycle-proteins-control-production-of-neutrophil-extracellular-traps
#17
Borko Amulic, Sebastian Lorenz Knackstedt, Ulrike Abu Abed, Nikolaus Deigendesch, Christopher J Harbort, Brian E Caffrey, Volker Brinkmann, Frank L Heppner, Philip W Hinds, Arturo Zychlinsky
Neutrophils are essential for immune defense and can respond to infection by releasing chromatin in the form of neutrophil extracellular traps (NETs). Here we show that NETs are induced by mitogens and accompanied by induction of cell-cycle markers, including phosphorylation of the retinoblastoma protein and lamins, nuclear envelope breakdown, and duplication of centrosomes. We identify cyclin-dependent kinases 4 and 6 (CDK4/6) as essential regulators of NETs and show that the response is inhibited by the cell-cycle inhibitor p21(Cip)...
October 31, 2017: Developmental Cell
https://www.readbyqxmd.com/read/29103175/efficacy-and-safety-in-older-patient-subsets-in-studies-of-endocrine-monotherapy-versus-combination-therapy-in-patients-with-hr-her2-%C3%A2-advanced-breast-cancer-a-review
#18
REVIEW
Rachel A Freedman, Sara M Tolaney
PURPOSE: Prospective information regarding the tolerability and efficacy of endocrine therapy (ET) alone and in combination with targeted agents in older patients in the metastatic setting is limited. This review summarizes available trial data in this population. METHODS: We searched PubMed for Phase 2 or 3 trials with age-stratified patient cohorts (≥ 65 vs. < 65 years in most studies) with hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) advanced breast cancer treated with ET ± targeted agents...
November 4, 2017: Breast Cancer Research and Treatment
https://www.readbyqxmd.com/read/29101163/cdk4-6-inhibition-augments-anti-tumor-immunity-by-enhancing-t-cell-activation
#19
Jiehui Deng, Eric S Wang, Russell W Jenkins, Shuai Li, Ruben Dries, Kathleen Yates, Sandeep Chhabra, Wei Huang, Hongye Liu, Amir R Aref, Elena Ivanova, Cloud Peter Paweletz, Michaela Bowden, Chensheng W Zhou, Grit S Herter-Sprie, Jessica A Sorrentino, John E Bisi, Patrick H Lizotte, Ashley A Merlino, Max M Quinn, Lauren E Bufe, Annan Yang, Yanxi Zhang, Hua Zhang, Peng Gao, Ting Chen, Megan E Cavanaugh, Amanda J Rode, Eric Haines, Patrick J Roberts, Jay C Strum, William G Richards, Jochen H Lorch, Sareh Parangi, Viswanath Gunda, Genevieve M Boland, Raphael Bueno, Sangeetha Palakurthi, Gordon J Freeman, Jerome Ritz, W Nicholas Haining, Norman E Sharpless, Haribabu Arthanari, Geoffrey I Shapiro, David A Barbie, Nathanael S Gray, Kwok-Kin Wong
Immune checkpoint blockade, exemplified by antibodies targeting the programmed death-1 (PD-1) receptor, can induce durable tumor regressions in some patients. To enhance the efficacy of existing immunotherapies, we screened for small molecules capable of increasing the activity of T cells suppressed by PD-1. Here, we show that short-term exposure to small molecule inhibitors of cyclin-dependent kinases 4 and 6 (CDK4/6) significantly enhances T cell activation, contributing to anti-tumor effects in vivo, due in part to de-repression of Nuclear Factor of Activated T cell (NFAT) family proteins and their target genes, critical regulators of T cell function...
November 3, 2017: Cancer Discovery
https://www.readbyqxmd.com/read/29100169/the-next-era-of-treatment-for-hormone-receptor-positive-her2-negative-advanced-breast-cancer-triplet-combination-based-endocrine-therapies
#20
REVIEW
Javier Cortés, Seock-Ah Im, Esther Holgado, Jose M Perez-Garcia, Peter Schmid, Mariana Chavez-MacGregor
Until recently, the standard of care for hormone receptor-positive (HR+) breast cancer was single-agent endocrine therapy, which aims to prevent estrogen receptor signaling. This therapeutic strategy has extended survival without the toxicity associated with chemotherapy, but primary endocrine therapy resistance is common, and secondary resistance develops over time. Adjunct downstream inhibition of the cyclin-dependent kinase (CDK)4/6 pathway, intended to delay and prevent endocrine therapy resistance, has further extended progression-free survival in patients receiving endocrine therapy; however, resistance still eventually develops in these patients...
October 12, 2017: Cancer Treatment Reviews
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