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Cdk 4/6

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https://www.readbyqxmd.com/read/29666673/pan-cdk-inhibition-augments-cisplatin-lethality-in-nasopharyngeal-carcinoma-cell-lines-and-xenograft-models
#1
Nicholas L Syn, Pei Li Lim, Li Ren Kong, Lingzhi Wang, Andrea Li-Ann Wong, Chwee Ming Lim, Thomas Kwok Seng Loh, Gerhard Siemeister, Boon Cher Goh, Wen-Son Hsieh
In addition to their canonical roles in regulating cell cycle transition and transcription, cyclin-dependent kinases (CDKs) have been shown to coordinate DNA damage response pathways, suggesting a rational pairing of CDK inhibitors with genotoxic chemotherapeutic agents in the treatment of human malignancies. Here, we report that roniciclib (BAY1000394), a potent pan-CDK inhibitor, displays promising anti-neoplastic activity as a single agent and potentiates cisplatin lethality in preclinical nasopharyngeal carcinoma (NPC) models...
2018: Signal Transduction and Targeted Therapy
https://www.readbyqxmd.com/read/29564743/a-gene-expression-signature-of-retinoblastoma-loss-of-function-predicts-resistance-to-neoadjuvant-chemotherapy-in-er-positive-her2-positive-breast-cancer-patients
#2
Emanuela Risi, Andrea Grilli, Ilenia Migliaccio, Chiara Biagioni, Amelia McCartney, Cristina Guarducci, Martina Bonechi, Matteo Benelli, Stefania Vitale, Laura Biganzoli, Silvio Bicciato, Angelo Di Leo, Luca Malorni
PURPOSE: HER2-positive (HER2+) breast cancers show heterogeneous response to chemotherapy, with the ER-positive (ER+) subgroup deriving less benefit. Loss of retinoblastoma tumor suppressor gene (RB1) function has been suggested as a cardinal feature of breast cancers that are more sensitive to chemotherapy and conversely resistant to CDK4/6 inhibitors. We performed a retrospective analysis exploring RBsig, a gene signature of RB loss, as a potential predictive marker of response to neoadjuvant chemotherapy in ER+/HER2+ breast cancer patients...
March 22, 2018: Breast Cancer Research and Treatment
https://www.readbyqxmd.com/read/29486476/voruciclib-a-potent-cdk4-6-inhibitor-antagonizes-abcb1-and-abcg2-mediated-multi-drug-resistance-in-cancer-cells
#3
Pranav Gupta, Yun-Kai Zhang, Xiao-Yu Zhang, Yi-Jun Wang, Kimberly W Lu, Timothy Hall, Richard Peng, Dong-Hua Yang, Ni Xie, Zhe-Sheng Chen
BACKGROUND/AIMS: The overexpression of ATP-Binding Cassette (ABC) transporters has known to be one of the major obstacles impeding the success of chemotherapy in drug resistant cancers. In this study, we evaluated voruciclib, a CDK 4/6 inhibitor, for its chemo-sensitizing activity in ABCB1- and ABCG2- overexpressing cells. METHODS: Cytotoxicity and reversal effect of voruciclib was determined by MTT assay. The intracellular accumulation and efflux of ABCB1 and ABCG2 substrates were measured by scintillation counter...
2018: Cellular Physiology and Biochemistry
https://www.readbyqxmd.com/read/29470723/cyclin-dependent-kinase-4-6-inhibitors-as-first-line-treatment-for-post-menopausal-metastatic-hormone-receptor-positive-breast-cancer-patients-a-systematic-review-and-meta-analysis-of-phase-iii-randomized-clinical-trials
#4
Allan Ramos-Esquivel, Hellen Hernández-Steller, Marie-France Savard, Denis Ulises Landaverde
BACKGROUND: To compare the efficacy and toxicity of the combination of cyclin-dependent kinase 4/6 (CDK 4/6) inhibitors and nonsteroidal aromatase inhibitors (AI) versus AI alone as first-line therapy for patients with advanced hormone receptor-positive breast cancer. MATERIALS AND METHODS: Phase III randomized clinical trials (RCT) were identified after a systematic review of electronic databases. A random-effect model was used to determine the pooled hazard ratio (HR) for progression-free survival (PFS) using the inverse-variance method...
February 22, 2018: Breast Cancer: the Journal of the Japanese Breast Cancer Society
https://www.readbyqxmd.com/read/29464035/upregulation-of-cell-cycle-genes-in-head-and-neck-cancer-patients-may-be-antagonized-by-erufosine-s-down-regulation-of-cell-cycle-processes-in-oscc-cells
#5
Shariq S Ansari, Ashwini K Sharma, Michael Zepp, Elizabet Ivanova, Frank Bergmann, Rainer König, Martin R Berger
The TCGA database was analyzed to identify deregulation of cell cycle genes across 24 cancer types and ensuing effects on patient survival. Pan-cancer analysis showed that head and neck squamous cell carcinoma (HNSCC) ranks amongst the top four cancers showing deregulated cell cycle genes. Also, the median gene expression of all CDKs and cyclins in HNSCC patient samples was higher than that of the global gene expression. This was verified by IHC staining of CCND1 from HNSCC patients. When evaluating the quartiles with highest and lowest expression, increased CCND1/CDK6 levels had negative implication on patient survival...
January 19, 2018: Oncotarget
https://www.readbyqxmd.com/read/29445290/molecular-features-of-giant-cell-carcinoma-of-the-lung-a-case-report-and-literature-review
#6
Xin Li, Zihe Zhang, Jinghao Liu, Dan Wang, Sen Wei, Jun Chen
Giant-cell carcinoma of the lung (GCCL) is a rare histological form of poorly differentiated non-small-cell lung cancer, which is classified as a subtype of pulmonary sarcomatoid carcinomas. In this case report, we describe the case of a 50-year-old Chinese male who presented with a pulmonary nodule in the right upper lobe of his lung. After thoracoscopic lobectomy, a histopathologic diagnosis of GCCL was made. He did well postoperatively, showing no local recurrence or distal disease in a 7-year follow-up period...
2018: OncoTargets and Therapy
https://www.readbyqxmd.com/read/29436583/antiproliferative-effects-of-the-cdk6-inhibitor-pd0332991-and-its-effect-on-signaling-networks-in-gastric-cancer-cells
#7
Daguang Wang, Yabin Sun, Wei Li, Fei Ye, Yang Zhang, Yuchen Guo, David Y Zhang, Jian Suo
PD0332991 (palbociclib/Ibrance®) is a cyclin-dependent kinase (CDK)4/6 inhibitor that has recently been approved for the treatment of estrogen receptor‑positive advanced breast cancer. The present study investigated the antiproliferative effects of PD0332991 on gastric cancer (GC) cells and the underlying molecular mechanisms. The activity of PD0332991 was tested in several GC cell lines, including AGS, KATO‑Ⅲ, NCI‑N87 and HS746T. Growth inhibitory activity of PD0332991, alone or in combination with fluorouracil (5‑FU), was measured by MTT assay...
February 6, 2018: International Journal of Molecular Medicine
https://www.readbyqxmd.com/read/29429832/design-and-synthesis-of-4-2-3-dihydro-1h-benzo-d-pyrrolo-1-2-a-imidazol-7-yl-n-5-piperazin-1-ylmethyl-pyridine-2-yl-pyrimidin-2-amine-as-a-highly-potent-and-selective-cyclin-dependent-kinases-4-and-6-inhibitors-and-the-discovery-of-structure-activity-relationships
#8
Yan Wang, Wen-Jian Liu, Lei Yin, Heng Li, Zhen-Hua Chen, Dian-Xi Zhu, Xiu-Qing Song, Zhen-Zhen Cheng, Peng Song, Zhan Wang, Zhi-Gang Li
Cyclin-dependent kinases 4/6 play an important role in regulation of cell cycle, and overexpress in a variety of cancers. Up to now, new CDK inhibitors still need to be developed due to its poor selectivity. Herein we report a novel series of 4-(2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazole-7-yl)-N-(5-(piperazin-1-ylmethyl)pyridine-2-yl)pyrimidin-2-amine anologues as potent CDK 4/6 inhibitors based on LY2835219 (Abemaciclib). Compound 10d, which exhibits approximate potency on CDK4/6 (IC50 = 7.4/0.9 nM), has both good pharmacokinetic characters and high selectivity on CDK1 compared with LY2835219...
January 31, 2018: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/29416931/single-oral-dose-acute-and-subacute-toxicity-of-a-c-met-tyrosine-kinase-inhibitor-and-cdk-4-6-inhibitor-combination-drug-therapy
#9
Brian Smith, Yi-Hsin Hsu, Rene Flores, Mihai Gagea, Suzanne Craig, Mien-Chie Hung
c-MET inhibitor, crizotinib, and CDK 4/6 inhibitor, palbociclib, have been evaluated in combination as cancer treatment in vitro. Because the toxicological data for the combination of these drugs is limited, we investigated the toxicity of the crizotinib and palbociclib combination in 80 ICR (CD-1) mice (average age = ~20 weeks). Treatments were arranged as a 2 × 2 × 2 factorial and included sex (female vs. male), crizotinib (0 or 4 mg), and palbociclib (0 or 1 mg). Drugs were administered to mice by oral gavage 24 hours (n = 40) and 7 days (n = 40) prior to the collection of blood and tissue samples to determine serum chemistry, hematology, and histopathology...
2018: American Journal of Cancer Research
https://www.readbyqxmd.com/read/29388072/pharmacotherapeutic-management-of-breast-cancer-in-elderly-patients-the-promise-of-novel-agents
#10
REVIEW
Catherine Terret, Chiara Russo
As its incidence increases with age, breast cancer in elderly patients takes on a growing importance in clinical oncology practice. Management decisions are challenging because there is a lack of high-quality evidence in this heterogeneous population. Epidemiological studies have shown that breast cancer mortality does not decrease substantially in the older population compared with younger adults. Recent data suggest a phenotype somewhat different from that of younger patients, also confirmed at the molecular level...
January 31, 2018: Drugs & Aging
https://www.readbyqxmd.com/read/29370702/discovery-and-preclinical-development-of-iiim-290-an-orally-active-potent-cyclin-dependent-kinase-inhibitor
#11
Sandip B Bharate, Vikas Kumar, Shreyans K Jain, Mubashir Javeed Mintoo, Santosh Kumar Guru, Vijay K Nuthakki, Mohit Sharma, Sonali S Bharate, Sumit G Gandhi, Dilip Manikrao Mondhe, Shashi Bhushan, Ram A Vishwakarma
Rohitukine (1), a chromone alkaloid isolated from Indian medicinal plant Dysoxylum binectariferum has inspired the discovery of flavopiridol and riviciclib, both of which are bioavailable only via IV route. With the objective to address oral bioavailability issue of this scaffold, four series of rohitukine derivatives were prepared and screened for Cdk inhibition and cellular antiproliferative activity. The 2,6-dichloro-styryl derivative IIIM-290 (11d) showed strong inhibition of Cdk-9/T1 (IC50 1.9 nM) kinase and Molt-4/MIAPaCa-2 cell growth (GI50 < 1...
January 25, 2018: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/29349762/advances-in-endocrine-therapy-for-postmenopausal-metastatic-breast-cancer
#12
Lisa E Flaum, William J Gradishar
A majority of breast cancers are hormone receptor (HR) positive and are responsive to various types of hormone manipulation. Endocrine therapy is the preferred first-line therapy for patients with advanced estrogen receptor (ER) positive, HER2-negative breast cancer who do not have symptomatic visceral disease. Endocrine therapy is often continued in the second- and third-line setting, with chemotherapy deferred until tumor becomes endocrine therapy refractory and/or a visceral crisis in imminent. Therapeutic options vary based on clinical presentation and include single-agent therapies such as tamoxifen, aromatase inhibitors and fulvestrant, and combination therapies options...
2018: Cancer Treatment and Research
https://www.readbyqxmd.com/read/29347968/-18-f-fdg-pet-ct-and-diffusion-weighted-mri-for-monitoring-a-braf-and-cdk-4-6-inhibitor-combination-therapy-in-a-murine-model-of-human-melanoma
#13
Ralf S Eschbach, Philipp M Kazmierczak, Maurice M Heimer, Andrei Todica, Heidrun Hirner-Eppeneder, Moritz J Schneider, Georg Keinrath, Olga Solyanik, Jessica Olivier, Wolfgang G Kunz, Maximilian F Reiser, Peter Bartenstein, Jens Ricke, Clemens C Cyran
BACKGROUND: The purpose of the study was to investigate a novel BRAF and CDK 4/6 inhibitor combination therapy in a murine model of BRAF-V600-mutant human melanoma monitored by 18 F-FDG-PET/CT and diffusion-weighted MRI (DW-MRI). METHODS: Human BRAF-V600-mutant melanoma (A375) xenograft-bearing balb/c nude mice (n = 21) were imaged by 18 F-FDG-PET/CT and DW-MRI before (day 0) and after (day 7) a 1-week BRAF and CDK 4/6 inhibitor combination therapy (n = 12; dabrafenib, 20 mg/kg/d; ribociclib, 100 mg/kg/d) or placebo (n = 9)...
January 18, 2018: Cancer Imaging: the Official Publication of the International Cancer Imaging Society
https://www.readbyqxmd.com/read/29335521/non-canonical-roles-of-pfkfb3-in-regulation-of-cell-cycle-through-binding-to-cdk4
#14
Wenzhi Jia, Xiaoping Zhao, Li Zhao, Hui Yan, Jiajin Li, Hao Yang, Gang Huang, Jianjun Liu
There is growing interest in studying the molecular mechanisms of crosstalk between cancer metabolism and the cell cycle. 6-phosphate fructose-2-kinase/fructose-2,6-bisphosphatase-3 (PFKFB3) is a well-known glycolytic activator that plays an important role in tumorigenesis. We investigated whether PFKFB3 was directly involved in oncogenic signaling networks. Mass Spectrometry showed that PFKFB3 interacts with cyclin-dependent kinase (CDK) 4, which controls the transition from G1 phase to S phase of the cell cycle...
March 2018: Oncogene
https://www.readbyqxmd.com/read/29311118/therapeutic-challenge-with-a-cdk-4-6-inhibitor-induces-an-rb-dependent-smac-mediated-apoptotic-response-in-non-small-cell-lung-cancer
#15
Chellappagounder Thangavel, Ettickan Boopathi, Yi Liu, Christopher McNair, Alex Haber, Maryna Perepelyuk, Anshul Bhardwaj, Sankar Addya, Adam Ertel, Sunday Shoyele, Ruth Birbe, Joseph M Salvino, Adam P Dicker, Karen E Knudsen, Robert B Den
Purpose: The retinoblastoma tumor suppressor (RB), a key regulator of cell-cycle progression and proliferation, is functionally suppressed in up to 50% of non-small cell lung cancer (NSCLC). RB function is exquisitely controlled by a series of proteins, including the CyclinD-CDK4/6 complex. In this study, we interrogated the capacity of a CDK4/6 inhibitor, palbociclib, to activate RB function. Experimental Design and Results: We employed multiple isogenic RB-proficient and -deficient NSCLC lines to interrogate the cytostatic and cytotoxic capacity of CDK 4/6 inhibition in vitro and in vivo We demonstrate that while short-term exposure to palbociclib induces cellular senescence, prolonged exposure results in inhibition of tumor growth...
March 15, 2018: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/29306020/a-selective-cyclin-dependent-kinase-4-6-dual-inhibitor-ribociclib-lee011-inhibits-cell-proliferation-and-induces-apoptosis-in-aggressive-thyroid-cancer
#16
Hyun Joo Lee, Woo Kyung Lee, Chan Woo Kang, Cheol Ryong Ku, Yoon Hee Cho, Eun Jig Lee
The RB-E2F1 pathway is an important mechanism of cell-cycle control, and deregulation of this pathway is one of the key factors contributing to tumorigenesis. Cyclin-dependent kinases (CDKs) and Cyclin D have been known to increase in aggressive thyroid cancer. However, there has been no study to investigate effects of a selective CDK 4/6 inhibitor, Ribociclib (LEE011), in thyroid cancer. Performing Western blotting, we found that RB phosphorylation and the expression of Cyclin D are significantly higher in papillary thyroid cancer (PTC) cell lines as well as anaplastic thyroid cancer (ATC) cell lines, compared with normal thyroid cell line and follicular thyroid cancer cell line...
March 28, 2018: Cancer Letters
https://www.readbyqxmd.com/read/29282688/cell-cycle-regulation-in-treatment-of-breast-cancer
#17
Zijie Cai, Qiang Liu
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...
2017: Advances in Experimental Medicine and Biology
https://www.readbyqxmd.com/read/29236940/polyclonal-rb1-mutations-and-acquired-resistance-to-cdk-4-6-inhibitors-in-patients-with-metastatic-breast-cancer
#18
R Condorelli, L Spring, J O'Shaughnessy, L Lacroix, C Bailleux, V Scott, J Dubois, R J Nagy, R B Lanman, A J Iafrate, F Andre, A Bardia
Background: While deregulation of the cyclin D1-CDK4/6-retinoblastoma pathway is common in hormone receptor positive (HR+) breast cancer, Rb is usually intact in HR+ breast cancer, and targeted CDK 4/6 inhibitors that act upstream of Rb, are routinely being utilized in clinical practice. However, factors that can lead to clinical resistance to CDK 4/6 inhibitors are not known. Patients and methods: We identified patients who had pre and post genotyping in tissue and peripheral blood samples after receiving CDK 4/6 inhibitors...
December 11, 2017: Annals of Oncology: Official Journal of the European Society for Medical Oncology
https://www.readbyqxmd.com/read/29234248/incorporating-cdk4-6-inhibitors-in-the-treatment-of-advanced-luminal-breast-cancer
#19
REVIEW
Isabel Echavarria, Yolanda Jerez, Miguel Martin, Sara López-Tarruella
After optimizing endocrine monotherapy modalities in the setting of advanced luminal breast cancer (BC), dual endocrine/targeted therapy combinations have been tested with positive results, and are transforming this BC subtype treatment landscape. Cell cycle deregulation is a hallmark of cancer that has become a key druggable target in hormone receptor (HR)-positive BC due to its role in endocrine resistance mechanisms. Cyclin dependent kinase (CDK)4/6 inhibitors have experienced a fast development in combination with endocrine therapy and have already been commercialized in some countries...
October 2017: Breast Care
https://www.readbyqxmd.com/read/29234247/pi3k-mtor-inhibitors-in-the-treatment-of-luminal-breast-cancer-why-when-and-to-whom
#20
REVIEW
Francesco Schettini, Giuseppe Buono, Meghana V Trivedi, Sabino De Placido, Grazia Arpino, Mario Giuliano
Estrogen receptor (ER) signaling represents the main driver of tumor growth and survival in luminal breast cancer (BC). Despite the efficacy of endocrine agents, many patients with luminal BC do not respond to endocrine therapy and many others develop endocrine resistance over time, due to the activation of escape pathways such as the PI3K/AKT/mTOR signaling. Several clinical trials have demonstrated the efficacy of mTOR and PI3K inhibitors in overcoming endocrine resistance in hormone receptor-positive human epidermal growth factor receptor 2 (HER2)-negative metastatic BC (MBC) patients...
October 2017: Breast Care
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