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CDK4/6 AND cancer

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https://www.readbyqxmd.com/read/29164917/efficacy-and-safety-of-palbociclib-in-heavily-pretreated-patients-with-hr-her2-%C3%A2-metastatic-breast-cancer
#1
Marija Ban, Branka Petrić Miše, Ana Majić, Ivanka Dražić, Eduard Vrdoljak
AIM: CDK4/6 inhibitors in the first and second treatment line in patients with HR+/HER2- metastatic breast cancer (mBC) in combination with hormonal therapy improve progression free survival. Role of CDK4/6 inhibitors in further treatment lines remains unclear. METHODS: Retrospective analysis of 24 HR+/HER2- heavily pretreated mBC patients is presented. RESULTS: A total of 58.3% patients achieved stable disease. No objective response was observed...
November 22, 2017: Future Oncology
https://www.readbyqxmd.com/read/29162134/serum-thymidine-kinase-1-activity-as-a-pharmacodynamic-marker-of-cyclin-dependent-kinase-4-6-inhibition-in-patients-with-early-stage-breast-cancer-receiving-neoadjuvant-palbociclib
#2
Nusayba Bagegni, Shana Thomas, Ning Liu, Jingqin Luo, Jeremy Hoog, Donald W Northfelt, Matthew P Goetz, Andres Forero, Mattias Bergqvist, Jakob Karen, Magnus Neumüller, Edward M Suh, Zhanfang Guo, Kiran Vij, Souzan Sanati, Matthew Ellis, Cynthia X Ma
BACKGROUND: Thymidine kinase 1 (TK1) is a cell cycle-regulated enzyme with peak expression in the S phase during DNA synthesis, and it is an attractive biomarker of cell proliferation. Serum TK1 activity has demonstrated prognostic value in patients with early-stage breast cancer. Because cyclin-dependent kinase 4/6 (CDK4/6) inhibitors prevent G1/S transition, we hypothesized that serum TK1 could be a biomarker for CDK4/6 inhibitors. We examined the drug-induced change in serum TK1 as well as its correlation with change in tumor Ki-67 levels in patients enrolled in the NeoPalAna trial (ClinicalTrials...
November 21, 2017: Breast Cancer Research: BCR
https://www.readbyqxmd.com/read/29160310/cyclin-d-cdk4-kinase-destabilizes-pd-l1-via-cul3-spop-to-control-cancer-immune-surveillance
#3
Jinfang Zhang, Xia Bu, Haizhen Wang, Yasheng Zhu, Yan Geng, Naoe Taira Nihira, Yuyong Tan, Yanpeng Ci, Fei Wu, Xiangpeng Dai, Jianping Guo, Yu-Han Huang, Caoqi Fan, Shancheng Ren, Yinghao Sun, Gordon J Freeman, Piotr Sicinski, Wenyi Wei
Treatments that target immune checkpoints, such as the one mediated by programmed cell death protein 1 (PD-1) and its ligand PD-L1, have been approved for treating human cancers with durable clinical benefit(1,2). However, many cancer patients fail to respond to anti-PD-1/PD-L1 treatment, and the underlying mechanism(s) is not well understood(3-5). Recent studies revealed that response to PD-1/PD-L1 blockade might correlate with PD-L1 expression levels in tumor cells(6,7). Hence, it is important to mechanistically understand the pathways controlling PD-L1 protein expression and stability, which can offer a molecular basis to improve the clinical response rate and efficacy of PD-1/PD-L1 blockade in cancer patients...
November 16, 2017: Nature
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
#4
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
#5
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/29147869/hematological-adverse-effects-in-breast-cancer-patients-treated-with-cyclin-dependent-kinase-4-and-6-inhibitors-a-systematic-review-and-meta-analysis
#6
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/29143969/the-molecular-basis-of-cytotoxicity-of-%C3%AE-spinasterol-from-ganoderma-resinaceum-induction-of-apoptosis-and-overexpression-of-p53-in-breast-and-ovarian-cancer-cell-lines
#7
Nada K Sedky, Zaynab El Gammal, Amir E Wahba, Eman Mosad, Zahraa Y Waly, Amira Ali El-Fallal, Reem K Arafa, Nagwa El-Badri
OBJECTIVES: Despite advances in therapy of breast and ovarian cancers, they still remain among the most imperative causes of cancer death in women. The first can be considered one of the most widespread diseases among females, while the latter is more lethal and needs prompt treatment. Thus, the research field can still benefit from discovery of new compounds that can be of potential use in management of these grave illnesses. We hereby aimed to assess the antitumor activity of the phytosterol α-spinasterol isolated from Ganoderma resinaceum mushroom on human breast cancer cell lines (MCF-7, MDA-MB-231), as well as, on human ovarian cancer cell line (SKOV-3)...
November 16, 2017: Journal of Cellular Biochemistry
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
#8
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/29133590/genotoxic-damage-activates-the-ampk-%C3%AE-1-isoform-in-the-nucleus-via-ca2-camkk2-signaling-to-enhance-tumor-cell-survival
#9
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/29115462/hedyotis%C3%A2-diffusa-willd-inhibits-proliferation-and-induces-apoptosis-of-5%C3%A2-fu-resistant-colorectal-cancer-cells-by-regulating-the-pi3k-akt-signaling-pathway
#10
Qiongyu Li, Zijun Lai, Zhaokun Yan, Jun Peng, Yiyi Jin, Lihui Wei, Jiumao Lin
Hedyotis diffusa Willd (HDW) is a major component frequently used in Traditional Chinese Medicine for the clinical treatment of colorectal cancer (CRC) and its associated drug resistance. However, the underlying mechanism of HDW circumventing drug resistance of cancer cells remains to be elucidated. Cancer cell resistance to apoptosis and activation of the phosphatidylinositol‑3‑kinase (PI3K)/protein kinase B (AKT) signaling pathway have been implicated as major factors in the acquired resistance to chemotherapeutic anti‑cancer drugs...
October 26, 2017: Molecular Medicine Reports
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
#11
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/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
#12
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/29100169/the-next-era-of-treatment-for-hormone-receptor-positive-her2-negative-advanced-breast-cancer-triplet-combination-based-endocrine-therapies
#13
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
https://www.readbyqxmd.com/read/29097733/discovery-of-targetable-genetic-alterations-in-advanced-non-small-cell-lung-cancer-using-a-next-generation-sequencing-based-circulating-tumor-dna-assay
#14
Helei Hou, Xiaonan Yang, Jinping Zhang, Zhe Zhang, Xiaomei Xu, Xiaoping Zhang, Chuantao Zhang, Dong Liu, Weihua Yan, Na Zhou, Hongmei Zhu, Zhaoyang Qian, Zhuokun Li, Xiaochun Zhang
Next-generation sequencing (NGS)-based circulating tumor DNA (ctDNA) assays have provided a new method of identifying tumor-driving genes in patients with advanced non-small cell lung carcinoma (NSCLC), especially in those whose cancer tissues are unavailable or in those that have acquired treatment resistance. Here, we describe a total of 119 patients with advanced EGFR-TKI-naive NSCLC and 15 EGFR-TKI-resistant patients to identify somatic SNVs, small indels, CNVs and gene fusions in 508 tumor-related genes...
November 6, 2017: Scientific Reports
https://www.readbyqxmd.com/read/29090083/gastrointestinal-adverse-effects-of-cyclin-dependent-kinase-4-and-6-inhibitors-in-breast-cancer-patients-a-systematic-review-and-meta-analysis
#15
REVIEW
Kyrillus S Shohdy, Shaimaa Lasheen, Loay Kassem, Omar Abdel-Rahman
BACKGROUND: Cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors show promising results in metastatic breast cancer. However, an increased incidence of adverse events is remarkable. Among others, gastrointestinal (GI) involvement is of momentous impact on patients and their quality of life. METHODS: Our search included PubMed, ASCO, ESMO and SABCS databases. Randomized phase II/III trials in metastatic breast cancer receiving CDK4/6 inhibitors were identified and considered relevant based on providing a sufficient safety profile on the incidence of adverse GI effects...
November 2017: Therapeutic Advances in Drug Safety
https://www.readbyqxmd.com/read/29080858/tailored-first-line-and-second-line-cdk4-targeting-treatment-combinations-in-mouse-models-of-pancreatic-cancer
#16
Angela Chou, Danielle Froio, Adnan M Nagrial, Ashleigh Parkin, Kendelle J Murphy, Venessa T Chin, Dalia Wohl, Angela Steinmann, Rhys Stark, Alison Drury, Stacey N Walters, Claire Vennin, Andrew Burgess, Mark Pinese, Lorraine A Chantrill, Mark J Cowley, Timothy J Molloy, Nicola Waddell, Amber Johns, Sean M Grimmond, David K Chang, Andrew V Biankin, Owen J Sansom, Jennifer P Morton, Shane T Grey, Thomas R Cox, John Turchini, Jaswinder Samra, Stephen J Clarke, Paul Timpson, Anthony J Gill, Marina Pajic
OBJECTIVE: Extensive molecular heterogeneity of pancreatic ductal adenocarcinoma (PDA), few effective therapies and high mortality make this disease a prime model for advancing development of tailored therapies. The p16-cyclin D-cyclin-dependent kinase 4/6-retinoblastoma (RB) protein (CDK4) pathway, regulator of cell proliferation, is deregulated in PDA. Our aim was to develop a novel personalised treatment strategy for PDA based on targeting CDK4. DESIGN: Sensitivity to potent CDK4/6 inhibitor PD-0332991 (palbociclib) was correlated to protein and genomic data in 19 primary patient-derived PDA lines to identify biomarkers of response...
October 28, 2017: Gut
https://www.readbyqxmd.com/read/29073835/mir-9-induces-cell-arrest-and-apoptosis-of-oral-squamous-cell-carcinoma-via-cdk-4-6-pathway
#17
Anquan Shang, Wen-Ying Lu, Man Yang, Cheng Zhou, Hong Zhang, Zheng-Xin Cai, Wei-Wei Wang, Wan-Xiang Wang, Gui-Qi Wu
Oral cancer remains a major public concern with considerable socioeconomic impact in the world, especially in southeast Asia. Despite substantial advancements have been made in treating oral cancer, the five-year survival rate for OSCC remained undesirable, and 35-55% patients developed recurrence within two years even with multimodality therapeutic strategies. Hence, identification of novel biomarkers for diagnosis and evaluating clinical outcome is of vital importance. MicroRNAs are 22-24 nt non-coding RNAs that could bind to 3' UTR of target mRNAs, thereby inducing degradation of mRNA or inhibiting translation...
October 26, 2017: Artificial Cells, Nanomedicine, and Biotechnology
https://www.readbyqxmd.com/read/29061672/mir-6883-family-mirnas-target-cdk4-6-to-induce-g1-phase-cell-cycle-arrest-in-colon-cancer-cells
#18
Amriti R Lulla, Michael J Slifker, Yan Zhou, Avital Lev, Margret B Einarson, David T Dicker, Wafik S El-Deiry
CDK4/6 targeting is a promising therapeutic strategy under development for various tumor types. In this study, we used computational methods and TCGA dataset analysis to identify novel miRNAs that target CDK4/6 and exhibit potential for therapeutic development in colorectal cancer (CRC). The 3'UTR of CDK4/6 mRNAs are targeted by a family of miRNAs which includes miR-6883-5p, miR-149*, miR-6785-5p and miR-4728-5p. Ectopic expression of miR-6883-5p or miR-149* downregulated CDK4 and CDK6 levels in human CRC cells...
October 23, 2017: Cancer Research
https://www.readbyqxmd.com/read/29059492/a-phase-1-study-of-single-agent-ribociclib-in-japanese-patients-with-advanced%C3%A2-solid%C3%A2-tumors
#19
Toshihiko Doi, Becker Hewes, Tomoyuki Kakizume, Takeshi Tajima, Norifumi Ishikawa, Yasuhide Yamada
The cyclin D-CDK4/6-INK4-Rb pathway is frequently dysregulated in cancers. Ribociclib, an orally available, selective CDK4/6 inhibitor, demonstrated preliminary clinical activity in a phase 1 study in the United States and Europe for patients with solid tumors and lymphomas. The present study aimed to determine the single-agent maximum tolerated dose (MTD) and recommended dose for expansion (RDE) in Japanese patients with advanced solid tumors. Ribociclib safety, tolerability, pharmacokinetic profile, and preliminary antitumor activity were also assessed...
October 23, 2017: Cancer Science
https://www.readbyqxmd.com/read/29059158/raf-inhibitor-ly3009120-sensitizes-ras-or-braf-mutant-cancer-to-cdk4-6-inhibition-by-abemaciclib-via-superior-inhibition-of-phospho-rb-and-suppression-of-cyclin-d1
#20
S-H Chen, X Gong, Y Zhang, R D Van Horn, T Yin, L Huber, T F Burke, J Manro, P W Iversen, W Wu, S V Bhagwat, R P Beckmann, R V Tiu, S G Buchanan, S-B Peng
KRAS, NRAS and BRAF mutations are among the most important oncogenic drivers in many major cancer types, such as melanoma, lung, colorectal and pancreatic cancer. There is currently no effective therapy for the treatment of RAS mutant cancers. LY3009120, a pan-RAF and RAF dimer inhibitor advanced to clinical study has been shown to inhibit both RAS and BRAF mutant cell proliferation in vitro and xenograft tumor growth in vivo. Abemaciclib, a CDK4/6-selective inhibitor, is currently in phase III studies for ER-positive breast cancer and KRAS mutant lung cancer...
October 23, 2017: Oncogene
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