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Cdk4/6

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https://www.readbyqxmd.com/read/29027483/cdk4-6-blockade-in-breast-cancer-current-experience-and-future-perspectives
#1
Dimitrios Zardavas, Noam Pondé, Konstantinos Tryfonidis
Dysregulated cellular proliferation, one of the hallmarks of cancer, is mediated by aberrant activation of the cell cycle machinery through the biological effects of cyclin-dependent kinases (CDKs). The clinical development of non-selective CDK inhibitors failed due to combined lack of efficacy and excessive toxicity reported by clinical trials across different cancer types. The clinical development of second generation, CDK4/6-selective inhibitors, namely palbociclib, abemaciclib and ribociclib, led to practice-changing results in the setting of breast cancer...
October 13, 2017: Expert Opinion on Investigational Drugs
https://www.readbyqxmd.com/read/28993193/%C3%AE-lipoic-acid-inhibits-human-lung-cancer-cell-proliferation-through-grb2-mediated-egfr-downregulation
#2
Lan Yang, Ya Wen, Guoqing Lv, Yuntao Lin, Junlong Tang, Jingxiao Lu, Manqiao Zhang, Wen Liu, Xiaojuan Sun
BACKGROUND: Alpha lipoic acid (α -LA) is a naturally occurring antioxidant and metabolic enzyme co-factor. Recently, α -LA has been reported to inhibit the growth of various cancer cells, but the precise signaling pathways that mediate the effects of α -LA on non-small cell lung cancer (NSCLC) development remain unclear. METHODS: The CCK-8 assay was used to assess cell proliferation in NSCLC cell lines after α -LA treatment. The expression of growth factor receptor-bound protein 2 (Grb2), cyclin-dependent kinase (CDK)-2, CDK4, CDK6, Cyclin D3, Cyclin E1, Ras, c-Raf, epidermal growth factor receptor (EGFR), ERK1/2 and activated EGFR and ERK1/2 was evaluated by western blotting...
October 6, 2017: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/28983608/alterations-in-cyclin%C3%A2-d1-and-cyclin%C3%A2-dependent-kinase-4-expression-in-the-amygdalae-of-post%C3%A2-traumatic-stress-disorder-rats
#3
Ming Cong, Lili Wen, Fang Han, Yanhao Xu, Yuxiu Shi
The amygdalae are an important component of the human limbic system and exhibit a key role in emotional and behavioral reactions. Previous studies have demonstrated abnormal function and morphology in the amygdalae of post‑traumatic stress disorder (PTSD)‑like animal models, however the underlying molecular mechanisms remain elusive. The authors have previously demonstrated that PTSD induced increased apoptosis in the amygdala of PTSD‑like animals. Cyclin D1 and cyclin‑dependent kinase 4 (CDK4) are two important regulators of the cell cycle...
September 26, 2017: Molecular Medicine Reports
https://www.readbyqxmd.com/read/28978620/de-novo-myc-addiction-as-an-adaptive-response-of-cancer-cells-to-cdk4-6-inhibition
#4
Míriam Tarrado-Castellarnau, Pedro de Atauri, Josep Tarragó-Celada, Jordi Perarnau, Mariia Yuneva, Timothy M Thomson, Marta Cascante
Cyclin-dependent kinases (CDK) are rational cancer therapeutic targets fraught with the development of acquired resistance by tumor cells. Through metabolic and transcriptomic analyses, we show that the inhibition of CDK4/6 leads to a metabolic reprogramming associated with gene networks orchestrated by the MYC transcription factor. Upon inhibition of CDK4/6, an accumulation of MYC protein ensues which explains an increased glutamine metabolism, activation of the mTOR pathway and blunting of HIF-1α-mediated responses to hypoxia...
October 4, 2017: Molecular Systems Biology
https://www.readbyqxmd.com/read/28978559/fda-oks-abemaciclib-for-er-her2-breast-cancer
#5
(no author information available yet)
The FDA has approved abemaciclib for women with advanced or metastatic ER-positive, HER2-negative breast cancer whose disease has progressed on endocrine therapy. This is the third CDK4/6 inhibitor to get the agency's go-ahead in 2.5 years.
October 4, 2017: Cancer Discovery
https://www.readbyqxmd.com/read/28978004/detection-of-esr1-mutations-in-circulating-cell-free-dna-from-patients-with-metastatic-breast-cancer-treated-with-palbociclib-and-letrozole
#6
Rekha Gyanchandani, Karthik J Kota, Amruth R Jonnalagadda, Tanya Minteer, Beth A Knapick, Steffi Oesterreich, Adam M Brufsky, Adrian V Lee, Shannon L Puhalla
ESR1 mutations are frequently acquired in hormone-resistant metastatic breast cancer (MBC). CDK4/6 inhibition along with endocrine therapy is a promising strategy in hormone receptor-positive MBC. However, the incidence and impact of ESR1 mutations on clinical outcome in patients treated with CDK4/6 inhibitors have not been defined. In this study, we evaluated the frequency of ESR1 mutations in cfDNA from 16 patients with MBC undergoing palbociclib and letrozole therapy. Four common ESR1 mutations (D538G, Y537C, Y537N, and Y537S) were analyzed in serial blood draws using ddPCR...
September 15, 2017: Oncotarget
https://www.readbyqxmd.com/read/28961554/cdk4-6-inhibition-in-early-and-metastatic-breast-cancer-a-review
#7
REVIEW
A F de Groot, C J Kuijpers, J R Kroep
Breast cancer (BC) is responsible for 14% of cancer-related deaths in women [1]. Cyclin-dependent kinase (CDK) 4/6 inhibitors are a new class of selective drugs, offering an effective and tolerable treatment. CDK4/6 inhibitors induce cell cycle arrest in the G1 phase, and may thereby prevent tumour progression. Three CDK4/6 inhibitors have been tested in clinical BC trials: palbociclib, ribociclib, and abemaciclib. The Food and Drug Administration (FDA) and European Commission (EMA) have approved palbociclib for the treatment of patients HR+ HER2- locally advanced or metastatic BC (aBC) in combination with an aromatase inhibitor as initial therapy in postmenopausal women or in combination with fulvestrant in women who have received prior endocrine therapy...
September 20, 2017: Cancer Treatment Reviews
https://www.readbyqxmd.com/read/28947566/cytoplasmic-cyclin-e-mediates-resistance-to-aromatase-inhibitors-in-breast-cancer
#8
Iman Doostan, Cansu Karakas, Mehrnooh Kohansal, Kwang Hui Low, Matthew J Ellis, John A Olson, Vera Suman, Kelly Hunt, Stacy Moulder-Thompson, Khandan Keyomarsi
PURPOSE: Preoperative aromatase inhibitor (AI) therapy has demonstrated efficacy in hormone receptor (HR)-positive postmenopausal breast cancer. However, many patients have disease that is either intrinsically resistant to AIs or that responds initially but develops resistance after prolonged exposure. We have shown that patients with breast tumors expressing the deregulated forms of cyclin E (low molecular weight forms [LMW-E]) have poor overall survival. Herein, we hypothesize that LMW-E expression can identify HR-positive tumors that are unresponsive to neoadjuvant AI therapy due to the inability of AIs to induce a cytostatic effect...
September 25, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/28947417/combined-cdk4-6-and-pi3k%C3%AE-inhibition-is-synergistic-and-immunogenic-in-triple-negative-breast-cancer
#9
Zhi Ling Teo, Stephanie Versaci, Sathana Dushyanthen, Franco Caramia, Peter Savas, Chris Mintoff, Magnus Zethoven, Balaji Virassamy, Stephen J Luen, Grant A McArthur, Wayne A Phillips, Phillip K Darcy, Sherene Loi
New treatments for triple-negative breast cancer (TNBC) are urgently needed. Despite there being little evidence of clinical activity as single-agent therapies, we show that dual blockade of PI3Kα and CDK4/6 is synergistically effective against multiple RB1-wildtype TNBC models. Combined PI3Kα and CDK4/6 inhibition significantly increased apoptosis, cell cycle arrest, and tumor immunogenicity and generated immunogenic cell death in human TNBC cell lines. Combination treatment also significantly improved disease control in human xenograft models compared with either monotherapy...
September 25, 2017: Cancer Research
https://www.readbyqxmd.com/read/28947133/palbociclib-induced-autophagy-and-senescence-in-gastric-cancer-cells
#10
Claudio A Valenzuela, Leandro Vargas, Valentina Martinez, Sindy Bravo, Nelson E Brown
Targeting cyclin D-CDK4/6 kinase complexes has recently been shown to increase the survival of breast cancer patients with estrogen receptor positive breast tumors. Based on these outcomes, CDK4/6 inhibitors are currently being tested, alone o in combination with other drugs, in the treatment of other malignancies characterized by hyper-activation of cyclin D-CDK4/6 complexes. Nonetheless, a better understanding of the cellular processes that are implemented in response to CDK4/6 inhibition is necessary to expand the therapeutic window and confront the development of drug resistance...
September 23, 2017: Experimental Cell Research
https://www.readbyqxmd.com/read/28939653/first-line-abemaciclib-effective-in-er-breast-cancer
#11
(no author information available yet)
Interim data from the MONARCH3 study indicate that abemaciclib is an effective first-line therapy for advanced ER-positive, HER2-negative breast cancer. Adding the investigational CDK4/6 inhibitor to letrozole significantly improved patients' progression-free survival, compared with those given a placebo alongside endocrine therapy.
September 22, 2017: Cancer Discovery
https://www.readbyqxmd.com/read/28935119/effects-of-cdk-inhibitors-on-the-maturation-transcription-and-mpf-activity-of-porcine-oocytes
#12
Reza K Oqani, Tao Lin, Jae Eun Lee, So Yeon Kim, Jung Won Kang, Dong Il Jin
In mammals, cyclin-dependent kinases (CDKs) are involved in regulating both the cell cycle and transcription. Although CDK1 is known to act as the kinase subunit of maturation-promoting factor (MPF), the roles of the other CDKs in mammalian oocyte maturation are not yet understood. Here, we show that inhibition of various CDKs by small molecule inhibitors has different effects on the maturation and transcriptional activity of pig oocytes in vitro. Inhibition of CDK1 did not significantly affect cumulus cell expansion, but its kinase activity was necessary for germinal vesicle breakdown (GVBD)...
September 18, 2017: Reproductive Biology
https://www.readbyqxmd.com/read/28928828/screening-of-candidate-key-genes-associated-with-human-osteosarcoma-using-bioinformatics-analysis
#13
Kefeng Zhang, Jianwen Gao, Yong Ni
The aim of the present study was to identify the key genes associated with osteosarcoma (OS) using a bioinformatics approach. Microarray data (GSE36004) was downloaded from the Gene Expression Omnibus database, including 19 OS cell lines and 6 normal controls. Differentially expressed genes (DEGs) in the OS cell lines were identified using the Limma package, and differentially methylated regions were screened with methyAnalysis in R. Copy number analysis was performed and genes with copy number gains/losses were further screened using DNAcopy and cghMCR packages...
September 2017: Oncology Letters
https://www.readbyqxmd.com/read/28927034/cyclin-d3-deficiency-inhibits-skin-tumor-development-but-does-not-affect-normal-keratinocyte-proliferation
#14
Sung Hyun Lee, Xian Wang, Sun Hye Kim, Yongbaek Kim, Marcelo L Rodriguez-Puebla
Rearrangement and amplification of the D-type cyclin genes have been reported in human cancer. Previous studies have demonstrated that Ras-mediated skin tumorigenesis depends on pathways that act through cyclin D1 and D2; however, the role of cyclin D3 remains unknown. The present study demonstrates that cyclin D3 ablation does not affect keratinocyte proliferation, but instead increases apoptosis levels in the bulge region of the hair follicle. Consequently, cyclin D3 ablation reduces skin papilloma development in a Ras-dependent carcinogenesis model...
September 2017: Oncology Letters
https://www.readbyqxmd.com/read/28923217/current-challenges-in-the-management-of-breast-cancer-brain-metastases
#15
REVIEW
Ciara C O'Sullivan, Nicole N Davarpanah, Jame Abraham, Susan E Bates
Approximately 50% of patients with advanced human epidermal growth factor 2 (HER2)-positive breast cancer and triple-negative breast cancer (TNBC) ultimately develop breast cancer brain metastases (BCBM), which are associated with significant morbidity and mortality. The advent of HER2-directed therapy resulted in greatly improved survival outcomes, but unfortunately at the price of an increased cumulative incidence of BCBM. We review challenges in the management of BCBM, and potential treatment strategies, including novel agents such as poly-adenosine diphosphate (ADP) ribose polymerase (PARP) inhibitors (olaparib, veliparib), cyclin-dependent kinase 4/6 (CDK4/6) inhibitors (palbociclib, abemaciclib), and taxane derivatives (eg, ANG1005 and TPI-287)...
April 2017: Seminars in Oncology
https://www.readbyqxmd.com/read/28922542/a-diphenyldiselenide-derivative-induces-autophagy-via-jnk-in-htb-54-lung-cancer-cells
#16
Marta Díaz, Roncesvalles González, Daniel Plano, Juan Antonio Palop, Carmen Sanmartín, Ignacio Encío
Symmetric aromatic diselenides are potential anticancer agents with strong cytotoxic activity. In this study, the in vitro anticancer activities of a novel series of diarylseleno derivatives from the diphenyldiselenide (DPDS) scaffold were evaluated. Most of the compounds exhibited high efficacy for inducing cytotoxicity against different human cancer cell lines. DPDS 2, the compound with the lowest mean GI50 value, induced both caspase-dependent apoptosis and arrest at the G0 /G1 phase in acute lymphoblastic leucemia CCRF-CEM cells...
September 18, 2017: Journal of Cellular and Molecular Medicine
https://www.readbyqxmd.com/read/28918692/the-cyclin-dependent-kinase-4-6-inhibitor-abemaciclib-exerts-dose-dependent-cytostatic-and-cytocidal-effects-and-induces-autophagy-in-multiple-myeloma-cells
#17
Noriyoshi Iriyama, Hirotsugu Hino, Shota Moriya, Masaki Hiramoto, Yoshihiro Hatta, Masami Takei, Keisuke Miyazawa
The D-type cyclin (CCND)-cyclin-dependent kinase 4/6 (CDK4/6) complex has been implicated in multiple myeloma development. We investigated the biological activity of CDK4/6 inhibitor abemaciclib on cell growth and survival in three myeloma cell lines, KMS-12-PE, RPMI 8226, and IM-9. Abemaciclib inhibited myeloma cell growth in a dose-dependent manner in all cell lines, with significant differences seen at a concentration of 320 nM. Treatment with 1 μM abemaciclib increased the fraction of cells in the G0/G1 phase and decreased the fraction in the S-G2/M phases...
September 18, 2017: Leukemia & Lymphoma
https://www.readbyqxmd.com/read/28911822/structural-insights-of-cyclin-dependent-kinases-implications-in-design-of-selective-inhibitors
#18
REVIEW
Sourav Kalra, Gaurav Joshi, Anjana Munshi, Raj Kumar
There are around 20 Cyclin-dependent kinases (CDKs) known till date, and various research groups have reported their role in different types of cancer. The X-ray structures of some CDKs especially CDK2 was exploited in the past few years, and several inhibitors have been found, e.g., flavopiridol, indirubicin, roscovitine, etc., but due to the specificity issues of these inhibitors (binding to all CDKs), these were called as pan inhibitors. The revolutionary outcome of palbociclib in 2015 as CDK4/6 inhibitor added a new charm to the specific inhibitor design for CDKs...
September 4, 2017: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28903422/cdk4-6-inhibition-is-more-active-against-the-glioblastoma-proneural-subtype
#19
Ming Li, Aizhen Xiao, Desiree Floyd, Inan Olmez, Jeongwu Lee, Jakub Godlewski, Agnieszka Bronisz, Krishna P L Bhat, Erik P Sulman, Ichiro Nakano, Benjamin Purow
Glioblastoma (GBM) is the most common and lethal brain tumor. Gene expression profiling has classified GBM into distinct subtypes, including proneural, mesenchymal, and classical, and identifying therapeutic vulnerabilities of these subtypes is an extremely high priority. We leveraged The Cancer Genome Atlas (TCGA) data, in particular for microRNA expression, to seek druggable core pathways in GBM. The E2F1-regulated miR-17˜92 cluster and its analogs are shown to be highly expressed in proneural GBM and in GSC lines, suggesting the E2F cell cycle pathway might be a key driver in proneural GBM...
August 15, 2017: Oncotarget
https://www.readbyqxmd.com/read/28903138/improvement-of-genetic-testing-for-cutaneous-melanoma-in-countries-with-low-to-moderate-incidence-the-rule-of-2-vs-the-rule-of-3
#20
Juliette Delaunay, Ludovic Martin, Brigitte Bressac-de Paillerets, Gerard Duru, Olivier Ingster, Luc Thomas
Importance: Genetic testing for melanoma-prone mutation in France, a country with low to moderate incidence of melanoma, is proposed in cases with 2 invasive cutaneous melanomas and/or related cancers in the same patient, or in first- or second-degree relatives (rule of 2). In preclinical studies, these rules led to disclosure of mutation(s) in more than 10% of these families, the threshold widely accepted to justify genetic testing for cancers. Objective: To reconsider these criteria in a general population testing of patients...
September 13, 2017: JAMA Dermatology
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