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https://www.readbyqxmd.com/read/29457921/ribociclib-for-the-treatment-of-hormone-receptor-positive-human-epidermal-growth-factor-receptor-2-negative-advanced-breast-cancer
#1
Howard A Burris
The emergence of cyclin-dependent kinases 4 and 6 (CDK4/6) inhibitors marked a significant advancement in the treatment of advanced breast cancer. Ribociclib is an orally bioavailable, highly selective inhibitor of CDK4/6. In combination with various endocrine therapies, ribociclib has demonstrated clinical activity as a first-line therapy for patients with HR+, HER2- advanced breast cancer, without compromising the favorable toxicity profile associated with endocrine therapy. Thus, ribociclib is now considered a new standard of care for HR+, HER2- advanced breast cancer...
March 2018: Expert Review of Anticancer Therapy
https://www.readbyqxmd.com/read/29452249/expression-and-therapeutic-implications-of-cyclin-dependent-kinase-4-cdk4-in-osteosarcoma
#2
Yubing Zhou, Jacson K Shen, Zujiang Yu, Francis J Hornicek, Quancheng Kan, Zhenfeng Duan
Overexpression and/or hyperactivation of cyclin-dependent kinase 4 (CDK4) has been found in many types of human cancers, and a CDK4 specific inhibitor, palbociclib, has been recently approved by the FDA for the treatment of breast cancer. However, the expression and the therapeutic potential of CDK4 in osteosarcoma remain unclear. In the present study, CDK4 was found to be highly expressed in human osteosarcoma tissues and cell lines as compared with normal human osteoblasts. Elevated CDK4 expression correlated with metastasis potential and poor prognosis in osteosarcoma patients as determined by immunohistochemical analysis in a human osteosarcoma tissue microarray (TMA)...
February 13, 2018: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/29437706/targeting-cyclin-d-cdk4-6-sensitizes-immune-refractory-cancer-by-blocking-the-scp3-nanog-axis
#3
Se Jin Oh, Hanbyoul Cho, Suhyun Kim, Kyung Hee Noh, Kwon-Ho Song, Hyo-Jung Lee, Seon Rang Woo, Suyeon Kim, Chel Hun Choi, Joon-Yong Chung, Stephen M Hewitt, Jae-Hoon Kim, Seungki Baek, Kyung-Mi Lee, Cassian Yee, Hae-Chul Park, Tae Woo Kim
Immune editing caused by anti-tumor immunity drives tumor cells to acquire refractory phenotypes. We demonstrated previously that tumor antigen-specific T cells edit these cells such that they become resistant to CTL killing and enrich NANOGhigh cancer stem cell-like (CSC-like) cells. In the current study, we show that synaptonemal complex protein 3 (SCP3), a member of the Cor1 family, is overexpressed in immune-edited cells and upregulates NANOG by hyperactivating the Cyclin D1-CDK4/6 axis. The SCP3-Cyclin D1-CDK4/6 axis was preserved across various types of human cancer, and correlated negatively with progression-free survival of cervical cancer patients...
February 6, 2018: Cancer Research
https://www.readbyqxmd.com/read/29435940/mechanism-and-method-for-generating-tumor-free-ips-cells-using-intronic-microrna-mir-302-induction
#4
Shi-Lung Lin, Shao-Yao Ying
Today's researchers generating induced pluripotent stem cells (iPS cells or iPSCs) usually consider their pluripotency rather than potential tumorigenicity. Oncogenic factors such as c-Myc and Klf4 are frequently used to boost the survival and proliferative rates of iPSCs, creating an inevitable problem of tumorigenicity that hinders the therapeutic usefulness of these iPSCs. To prevent stem cell tumorigenicity, we have examined mechanisms by which the cell cycle genes are regulated in embryonic stem cells (ESCs)...
2018: Methods in Molecular Biology
https://www.readbyqxmd.com/read/29434218/association-of-cytosolic-sialidase-neu2-with-plasma-membrane-enhances-fas-mediated-apoptosis-by-impairing-pi3k-akt-mtor-mediated-pathway-in-pancreatic-cancer-cells
#5
Shalini Nath, Chhabinath Mandal, Uttara Chatterjee, Chitra Mandal
Modulation of sialylation by sialyltransferases and sialidases plays essential role in carcinogenesis. There are few reports on sialyltransferase, however, the contribution of cytosolic sialidase (Neu2) remains unexplored in pancreatic ductal adenocarcinoma (PDAC). We observed lower expression of Neu2 in different PDAC cells, patient tissues, and a significant strong association with clinicopathological characteristics. Neu2 overexpression guided drug-resistant MIAPaCa2 and AsPC1 cells toward apoptosis as evidenced by decreased Bcl2/Bax ratio, activation of caspase-3/caspase-6/caspase-8, PARP reduction, reduced CDK2/CDK4/CDK6, and cyclin-B1/cyclin-E with unaffected caspase-9...
February 12, 2018: Cell Death & Disease
https://www.readbyqxmd.com/read/29431643/epigenetic-dysregulation-of-the-drp1-binding-partners-mid49-and-mid51-increases-mitotic-mitochondrial-fission-and-promotes-pulmonary-arterial-hypertension-mechanistic-and-therapeutic-implications
#6
Kuang-Hueih Chen, Asish Dasgupta, Jianhui Lin, Francois Potus, Sebastien Bonnet, James Iremonger, Jennifer Fu, Jeffrey Mewburn, Danchen Wu, Kimberly Dunham-Snary, Anne L Theilmann, Zhi-Cheng Jing, Charles Hindmarch, Mark L Ormiston, Allan Lawrie, Stephen L Archer
Background -Mitotic fission is increased in pulmonary arterial hypertension (PAH), a hyperproliferative, apoptosis-resistant disease. The fission mediator, dynamin related protein 1 (Drp1) must complex with adaptor proteins to cause fission. Drp1-induced fission has been therapeutically targeted in experimental PAH. Here we examine the role of two recently discovered, poorly understood, Drp1 adapter proteins, mitochondrial dynamics protein of 49 and 51 kDa (MiD49 and MiD51) in normal vascular cells and explore their dysregulation in PAH...
February 5, 2018: Circulation
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
#7
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/29429159/-retroperitoneal-dedifferentiated-liposarcoma-with-rhabdomyoblastic-differentiation-a-clinicopathological-analysis
#8
L Liu, L H Wang, Y B Ren, X S Rao, S M Yang
Objective: To investigate the clinicopathological features, differential diagnosis, treatment and prognosis of dedifferentiated liposarcoma with rhabdomyoblastic differentiation. Methods: Six cases of retroperitoneal dedifferentiated liposarcoma with rhabdomyoblastic features were collected from December 2014 to August 2017 at Peking University International Hospital. The clinical manifestations, histomorphology, immunophenotype, treatment and follow-up data were analyzed, and relevant literature reviewed. Results: The six patients included two males and four females, with age range of 47 to 66 years (mean 56 years)...
February 8, 2018: Zhonghua Bing Li Xue za Zhi Chinese Journal of Pathology
https://www.readbyqxmd.com/read/29408328/ribociclib-a-cdk4-cdk6-kinase-inhibitor-enhances-glucocorticoid-sensitivity-in-b-acute-lymphoblastic-leukemia-b-all
#9
Roberta Bortolozzi, Elena Mattiuzzo, Luca Trentin, Benedetta Accordi, Giuseppe Basso, Giampietro Viola
Dysregulation of the cyclin D1-CDK4/CDK6 complex is frequently observed in almost all human cancer and contributes to aberrant cell proliferation and consequent tumorigenesis. Although many reports described the importance of CDK4/CDK6 in different set of human tumors, only few studies have been performed on leukemia. By gene expression analysis performed in a cohort of childhood patients affected by B-acute lymphoblastic leukemia (B-ALL) we found that both CDK4 and CDK6 are highly expressed. Moreover, Reverse Phase Protein Array (RPPA) analysis showed that cyclin D1 levels are higher in patients undergoing relapse...
February 3, 2018: Biochemical Pharmacology
https://www.readbyqxmd.com/read/29399694/mechanisms-of-the-cdk4-6-inhibitor-palbociclib-pd-0332991-and-its-future-application-in-cancer-treatment-review
#10
Minghui Liu, Hongyu Liu, Jun Chen
An uncontrolled cell cycle is an obvious marker of tumor cells. The G1‑S phase is an important restriction point in the normal cell cycle, but in cancer cells the restriction function is reduced, leading to uncontrolled cell proliferation. Two cyclin‑dependent kinases (CDKs), CDK4 and CDK6, play a crucial role in the G1‑S phase transition. Inhibitors of CDK4/6 are presently the subjects of numerous studies, and PD 0332991, an inhibitor of CDK4/6, has been used to treat hormone receptor (HR)‑positive, advanced‑stage breast cancer...
January 19, 2018: Oncology Reports
https://www.readbyqxmd.com/read/29392622/clinical-development-of-cdk4-6-inhibitor-for-breast-cancer
#11
Hiroji Iwata
Endocrine therapy is the mainstay of treatment for patients with estrogen receptor positive (ER+)/HER2-negative (HER2-) metastatic breast cancer (MBC). Many clinicians consider the sequential endocrine therapy is gold standard strategy because of better outcome and the maintenance of a better quality of life (QOL) for MBC patients. However, clinical practice shall be changed according to development of CDK4/6 inhibitor in current. CDK4/6 is key kinase which promote the cell cycle, and especially the expression of cyclin D1 and the activation of CDK4/6 to drive breast cancer proliferation...
February 1, 2018: Breast Cancer: the Journal of the Japanese Breast Cancer Society
https://www.readbyqxmd.com/read/29386107/targeting-the-vulnerability-of-rb-tumor-suppressor-loss-in-triple-negative-breast-cancer
#12
Agnieszka K Witkiewicz, Sejin Chung, Rachel Brough, Paris Vail, Jorge Franco, Christopher J Lord, Erik S Knudsen
Approximately 30% of triple-negative breast cancers (TNBCs) exhibit functional loss of the RB tumor suppressor, suggesting a target for precision intervention. Here, we use drug screens to identify agents specifically antagonized by the retinoblastoma tumor suppressor (RB) using CDK4/6 inhibitors. A number of candidate RB-synthetic lethal small molecules were identified, including anti-helmenthics, chemotherapeutic agents, and small-molecule inhibitors targeting DNA-damage checkpoints (e.g., CHK) and chromosome segregation (e...
January 30, 2018: Cell Reports
https://www.readbyqxmd.com/read/29372101/cell-cycle-regulation-and-anticancer-drug-discovery
#13
Jingwen Bai, Yaochen Li, Guojun Zhang
Cellular growth, development, and differentiation are tightly controlled by a conserved biological mechanism: the cell cycle. This cycle is primarily regulated by cyclin-dependent kinase (CDK)-cyclin complexes, checkpoint kinases, and CDK inhibitors. Deregulation of the cell cycle is a hallmark of the transformation of normal cells into tumor cells. Given its importance in tumorigenesis, several cell cycle inhibitors have emerged as potential therapeutic drugs for the treatment of cancers-both as single-agent therapy and in combination with traditional cytotoxic or molecular targeting agents...
November 2017: Cancer Biology & Medicine
https://www.readbyqxmd.com/read/29371923/targeting-the-pttg1-oncogene-impairs-proliferation-and-invasiveness-of-melanoma-cells-sensitive-or-with-acquired-resistance-to-the-braf-inhibitor-dabrafenib
#14
Simona Caporali, Ester Alvino, Pedro Miguel Lacal, Federica Ruffini, Lauretta Levati, Laura Bonmassar, Alessandro Scoppola, Paolo Marchetti, Simona Mastroeni, Gian Carlo Antonini Cappellini, Stefania D'Atri
The pituitary tumor transforming gene 1 (PTTG1) is implicated in tumor growth, metastasis and drug resistance. Here, we investigated the involvement of PTTG1 in melanoma cell proliferation, invasiveness and response to the BRAF inhibitor (BRAFi) dabrafenib. We also preliminary assessed the potential value of circulating PTTG1 protein to monitor melanoma patient response to BRAFi or to dabrafenib plus trametinib. Dabrafenib-resistant cell lines (A375R and SK-Mel28R) were more invasive than their drug-sensitive counterparts (A375 and SK-Mel28), but expressed comparable PTTG1 levels...
December 26, 2017: Oncotarget
https://www.readbyqxmd.com/read/29364969/contribution-of-oxidative-stress-and-growth-factor-receptor-transactivation-in-natriuretic-peptide-receptor-c-mediated-attenuation-of-hyperproliferation-of-vascular-smooth-muscle-cells-from-shr
#15
Sofiane Rahali, Yuan Li, Madhu B Anand-Srivastava
Earlier studies have shown the implication of growth factor receptor activation in angiotensin II (Ang II)-induced hyperproliferation of aortic VSMC as well as in hyperproliferation of VSMC from spontaneously hypertensive rats (SHR). We previously showed that NPR-C specific agonist C-ANP4-23 attenuates the hyperproliferation of VSMC from SHR through the inhibition of MAP kinase, Giα protein signaling and overexpression of cell cycle proteins. The aim of the present study was to investigate if C-ANP4-23- mediated attenuation of hyperproliferation of VSMC from SHR also involves growth factor receptor activation and upstream signaling molecules...
2018: PloS One
https://www.readbyqxmd.com/read/29352052/estrogen-receptor-positive-breast-cancer-exploiting-signaling-pathways-implicated-in-endocrine-resistance
#16
REVIEW
Adam M Brufsky, Maura N Dickler
Advancements in molecular profiling and endocrine therapy (ET) have led to more focused clinical attention on precision medicine. These advances have expanded our understanding of breast cancer (BC) pathogenesis and hold promising implications for the future of therapy. The estrogen receptor-α is a predominant endocrine regulatory protein in the breast and in estrogen-induced BC. Successful targeting of proteins and genes within estrogen receptor (ER) nuclear and nonnuclear pathways remains a clinical goal...
January 19, 2018: Oncologist
https://www.readbyqxmd.com/read/29349755/adjuvant-endocrine-therapy
#17
Rena Shah, Ruth M O'Regan
The use of hormonal therapy in breast cancer has improved the overall outcome for patients with early-stage hormone receptor-positive disease. The choice of hormone therapy is related to multiple factors, including menopausal state, patient preference, and potential side effects. Molecular profiling has allowed therapy to be tailored for an individual patient to some extent. However, further molecular studies are needed to individualize the choice and length of adjuvant hormone therapy. Ongoing studies are evaluating the role of additional targeted therapies, such as CDK4/6 inhibitors, to further improve outcome for patients with early-stage hormone receptor-positive breast cancer...
2018: Cancer Treatment and Research
https://www.readbyqxmd.com/read/29337271/rfrp-3-the-mammalian-ortholog-of-gnih-induces-cell-cycle-arrest-at-g2-m-in-porcine-ovarian-granulosa-cells
#18
Xiaoye Wang, Xun Li, Chuanhuo Hu
RFamide-related peptide-3 (RFRP-3), the mammalian ortholog of gonadotropin-inhibitory hormone (GnIH), has been proposed as a key inhibitory regulator of mammal reproduction. Our previous studies have demonstrated that RFRP-3 inhibited the expression of proliferation-related proteins in porcine granulose cells (GCs), but the inhibitory mechanism causing this has not been discovered. Here, we aim to elucidate the underlying mechanism and determine the cell cycle regulatory sites of action of RFRP-3 on porcine GC proliferation...
January 11, 2018: Peptides
https://www.readbyqxmd.com/read/29335521/non-canonical-roles-of-pfkfb3-in-regulation-of-cell-cycle-through-binding-to-cdk4
#19
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...
January 16, 2018: Oncogene
https://www.readbyqxmd.com/read/29330290/dual-inhibition-of-cdk4-and-cdk2-via-targeting-p27-tyrosine-phosphorylation-induces-a-potent-and-durable-response-in-breast-cancer-cells
#20
Priyank Patel, Vladislav Tsiperson, Susan R S Gottesman, Jonathan Somma, Stacy W Blain
Cyclin-dependent kinase 4/6 (CDK4/6)-specific inhibitors, such as palbociclib, have shown clinical efficacy, but primary or secondary resistance has emerged as a problem. To develop more effective therapeutic approaches, investigation is needed into the mechanisms of resistance or adaption. Here, it is demonstrated that CDK2 compensates for loss of CDK4 activity to rescue palbociclib-arrested breast cancer cells, suggesting that inhibition of both kinases is required to achieve durable response. In addition, a novel strategy is described to inhibit tyrosine phosphorylation of p27Kip1 (CDKN1B) and simultaneously inhibit both CDK2 and CDK4...
January 12, 2018: Molecular Cancer Research: MCR
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