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https://www.readbyqxmd.com/read/29243224/palbociclib-synergizes-with-braf-and-mek-inhibitors-in-treatment-na%C3%A3-ve-melanoma-but-not-after-the-development-of-braf-inhibitor-resistance
#1
Claire A Martin, Carleen Cullinane, Laura Kirby, Shatha Abuhammad, Emily J Lelliott, Kelly Waldeck, Richard J Young, Natalie Brajanovski, Donald P Cameron, Rachael Walker, Elaine Sanij, Gretchen Poortinga, Ross D Hannan, Richard B Pearson, Rodney J Hicks, Grant A McArthur, Karen E Sheppard
Increased CDK4 activity occurs in the majority of melanomas and CDK4/6 inhibitors in combination with BRAF and MEK inhibitors are currently in clinical trials for the treatment of melanoma. We hypothesize that the timing of the addition of CDK4/6 inhibitors to the current BRAF and MEK inhibitor regime will impact on the efficacy of this triplet drug combination. The efficacy of BRAF, MEK and CDK4/6 inhibitors as single agents and in combination were assessed in human BRAF mutant cell lines that were treatment naïve, BRAF inhibitor tolerant or had acquired resistance to BRAF inhibitors...
December 15, 2017: International Journal of Cancer. Journal International du Cancer
https://www.readbyqxmd.com/read/29236940/polyclonal-rb1-mutations-and-acquired-resistance-to-cdk-4-6-inhibitors-in-patients-with-metastatic-breast-cancer
#2
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/29236235/potential-biomarkers-of-cdk4-6-inhibitors-in-hormone-receptor-positive-advanced-breast-cancer
#3
REVIEW
Hehui Fang, Doudou Huang, Fang Yang, Xiaoxiang Guan
PURPOSE: Cyclin D/cyclin-dependent kinase 4/6 (CDK4/6) complex inhibitors have recently been proven effective when combined with endocrine therapy in clinical trials. However, the clinical benefit from CDK4/6 inhibitor varied from different patients. In order to optimize the clinical application of CDK4/6 inhibitors, this review focuses on the potential biomarkers applicable to identify patients who will benefit the most from CDK4/6 inhibition. METHODS: We have summarized the clinical trials about addition of CDK4/6 inhibitors to endocrine therapy and reviewed literature currently available on the potential biomarkers in predicting efficacy of CDK4/6 inhibitors...
December 13, 2017: Breast Cancer Research and Treatment
https://www.readbyqxmd.com/read/29234249/mechanisms-of-resistance-to-cdk4-6-inhibitors-in-breast-cancer-and-potential-biomarkers-of-response
#4
REVIEW
Cristina Guarducci, Martina Bonechi, Giulia Boccalini, Matteo Benelli, Emanuela Risi, Angelo Di Leo, Luca Malorni, Ilenia Migliaccio
Randomized clinical trials demonstrated that CDK4/6 inhibitors are highly effective in patients with hormone receptor-positive (HR+), HER2-negative (HER2-) metastatic breast cancer in combination with endocrine therapy. The use of CDK4/6 inhibitors in clinics is becoming common for patients with HR+/HER2- metastatic breast cancer and will certainly increase in the near future. However, patients might show de novo or acquired resistance to these drugs. Molecular alterations have been suggested as determinants for de novo resistance to CDK4/6 inhibitors, but have never been validated in a clinical setting...
October 2017: Breast Care
https://www.readbyqxmd.com/read/29234248/incorporating-cdk4-6-inhibitors-in-the-treatment-of-advanced-luminal-breast-cancer
#5
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/29232554/genomic-aberrations-that-activate-d-type-cyclins-are-associated-with-enhanced-sensitivity-to-the-cdk4-and-cdk6-inhibitor-abemaciclib
#6
Xueqian Gong, Lacey M Litchfield, Yue Webster, Li-Chun Chio, Swee Seong Wong, Trent R Stewart, Michele Dowless, Jack Dempsey, Yi Zeng, Raquel Torres, Karsten Boehnke, Cecilia Mur, Carlos Marugán, Carmen Baquero, Chunping Yu, Steven M Bray, Isabella H Wulur, Chen Bi, Shaoyou Chu, Hui-Rong Qian, Philip W Iversen, Farhana F Merzoug, Xiang S Ye, Christoph Reinhard, Alfonso De Dios, Jian Du, Charles W Caldwell, María José Lallena, Richard P Beckmann, Sean G Buchanan
Most cancers preserve functional retinoblastoma (Rb) and may, therefore, respond to inhibition of D-cyclin-dependent Rb kinases, CDK4 and CDK6. To date, CDK4/6 inhibitors have shown promising clinical activity in breast cancer and lymphomas, but it is not clear which additional Rb-positive cancers might benefit from these agents. No systematic survey to compare relative sensitivities across tumor types and define molecular determinants of response has been described. We report a subset of cancers highly sensitive to CDK4/6 inhibition and characterized by various genomic aberrations known to elevate D-cyclin levels and describe a recurrent CCND1 3'UTR mutation associated with increased expression in endometrial cancer...
December 11, 2017: Cancer Cell
https://www.readbyqxmd.com/read/29232548/genomic-biomarkers-predicting-response-to-selective-cdk4-6-inhibition-progress-in-an-elusive-search
#7
Geoffrey I Shapiro
In this issue of Cancer Cell, Gong et al. have analyzed the sensitivity of 560 cell lines to the selective CDK4/6 inhibitor abemaciclib and have defined cancers with specific genomic "D-cyclin activating features (DCAF)" as particularly vulnerable. These findings will facilitate patient selection as development of this drug class continues.
December 11, 2017: Cancer Cell
https://www.readbyqxmd.com/read/29232286/poorly-differentiated-esophageal-neuroendocrine-carcinoma-treated-with-the-cdk4-6-inhibitor-palbociclib-a-case-report-and-literature-review
#8
Yao Xu, Xia Li, Yu-Fen Xu, Xin-Mei Yang
No abstract text is available yet for this article.
November 27, 2017: American Journal of Therapeutics
https://www.readbyqxmd.com/read/29229752/ribociclib-extends-survival-in-hr-breast-cancer
#9
(no author information available yet)
Adding the CDK4/6 inhibitor ribociclib to standard first-line endocrine therapy significantly prolonged survival in premenopausal and perimenopausal women with advanced HR-positive, HER2-negative breast cancer enrolled in the MONALEESA-7 trial. This is the first definitive evidence that CDK4/6 inhibitor-based therapy is effective for first-line treatment of premenopausal and perimenopausal women.
December 11, 2017: Cancer Discovery
https://www.readbyqxmd.com/read/29221116/the-addition-of-abemaciclib-to-sunitinib-induces-regression-of-renal-cell-carcinoma-xenograft-tumors
#10
Jeffrey Small, Erik Washburn, Karmaine Millington, Junjia Zhu, Sheldon L Holder
Multiple therapies currently exist for renal cell carcinoma, however, most do not result in cure and the development of acquired resistance is the rule rather than the exception. CDK4/6 and PIM1 kinases are potential new therapeutic targets in RCC. Abemaciclib is a potent CDK4/6 and PIM1 kinase inhibitor, thus we evaluated the effects of abemaciclib on renal cell carcinoma. In vitro, abemaciclib causes decreased cellular viability, increased apoptosis, and alterations in autophagy in renal cell carcinoma cell lines...
November 10, 2017: Oncotarget
https://www.readbyqxmd.com/read/29218622/inhibiting-cdk-in-cancer-therapy-current-evidence-and-future-directions
#11
REVIEW
Smruthi Vijayaraghavan, Stacy Moulder, Khandan Keyomarsi, Rachel M Layman
Cell cycle dysregulation is a hallmark of all cancers, resulting in uncontrolled proliferation. Cyclin dependent kinases (CDKs), a family of proteins that are involved in the regulation of the cell cycle, are frequently overexpressed or mutated in cancer. Hence, CDK-inhibiting drugs have been developed and evaluated as cancer therapeutics. Clinical trials have shown CDK4/6 inhibitors (CDK4/6i) to be relatively safe and effective, and these are now standard of care treatment for advanced hormone receptor positive breast cancer...
December 7, 2017: Targeted Oncology
https://www.readbyqxmd.com/read/29203592/correction-of-gsk3%C3%AE-at-young-age-prevents-muscle-pathology-in-mice-with-myotonic-dystrophy-type-1
#12
Christina Wei, Lauren Stock, Leila Valanejad, Zachary A Zalewski, Rebekah Karns, Jack Puymirat, David Nelson, David Witte, Jim Woodgett, Nikolai A Timchenko, Lubov Timchenko
Myotonic dystrophy type 1 (DM1) is a progressive neuromuscular disease caused by expanded CUG repeats, which misregulate RNA metabolism through several RNA-binding proteins, including CUG-binding protein/CUGBP1 elav-like factor 1 (CUGBP1/CELF1) and muscleblind 1 protein. Mutant CUG repeats elevate CUGBP1 and alter CUGBP1 activity via a glycogen synthase kinase 3β (GSK3β)-cyclin D3-cyclin D-dependent kinase 4 (CDK4) signaling pathway. Inhibition of GSK3β corrects abnormal activity of CUGBP1 in DM1 mice [human skeletal actin mRNA, containing long repeats (HSALR ) model]...
December 4, 2017: FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology
https://www.readbyqxmd.com/read/29196468/cdk4-6-inhibitors-increase-pd-l1-expression
#13
(no author information available yet)
Cyclin D/CDK4 destabilize PD-L1 via the CUL3SPOP E3 ligase to increase tumor-infiltrating lymphocytes.
December 1, 2017: Cancer Discovery
https://www.readbyqxmd.com/read/29188531/mir-519d-3p-suppresses-breast-cancer-cell-growth-and-motility-via-targeting-lim-domain-kinase-1
#14
Dengfeng Li, Hongming Song, Tianqi Wu, Dan Xie, Jiashu Hu, Junyong Zhao, Qiang Shen, Lin Fang
Breast cancer is the most common female cancer in women, and its estrogen receptor (ER)-negative subtype (ENBC) and triple-negative subtype (TNBC) have unfavorable prognosis in comparison with ER-positive subtype. MiRNAs are small noncoding RNAs that bind to the 3'-UTR region of targeting mRNAs to regulate gene expression. Mir-519d-3p was found to be associated with breast cancer for its potential role in proliferation and metastasis. To explore its potential role and mechanism of miR-519d-3p in breast carcinogenesis, we determined whether miR-519d-3p regulates breast cancer cell proliferation and motility by performing wound-healing assays and migration-invasion assays...
November 29, 2017: Molecular and Cellular Biochemistry
https://www.readbyqxmd.com/read/29177689/expression-of-cyclin-d1-protein-in-residual-tumor-after-neoadjuvant-chemotherapy-for-breast-cancer
#15
S L Villegas, S Darb-Esfahani, G von Minckwitz, J Huober, K Weber, F Marmé, J Furlanetto, C Schem, B M Pfitzner, B Lederer, K Engels, S Kümmel, V Müller, K Mehta, C Denkert, S Loibl
PURPOSE: Hormone receptor (HR)-positive breast cancer (BC) shows a poor response to neoadjuvant chemotherapy (NACT). New treatment targets like the Cyclin D1-CDK4/CDK6 complex are promising adjuvant/post-neoadjuvant therapeutic strategies. Evaluating Cyclin D1 overexpression in residual tumor could recognize those patients that benefit most from such post-neoadjuvant treatment. In this study, we determined Cyclin D1 expression in residual BC after NACT. Secondary aims were to correlate Cyclin D1 expression levels with clinicopathological parameters and to assess its prognostic value after NACT...
November 25, 2017: Breast Cancer Research and Treatment
https://www.readbyqxmd.com/read/29164917/efficacy-and-safety-of-palbociclib-in-heavily-pretreated-patients-with-hr-her2-%C3%A2-metastatic-breast-cancer
#16
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
#17
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
#18
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
#19
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
#20
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
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