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Cdk4 inhibitor

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https://www.readbyqxmd.com/read/28092667/oncogenic-braf-fusions-in-mucosal-melanomas-activate-the-mapk-pathway-and-are-sensitive-to-mek-pi3k-inhibition-or-mek-cdk4-6-inhibition
#1
H S Kim, M Jung, H N Kang, H Kim, C-W Park, S-M Kim, S J Shin, S H Kim, S G Kim, E K Kim, M R Yun, Z Zheng, K Y Chung, J Greenbowe, S M Ali, T-M Kim, B C Cho
Despite remarkable progress in cutaneous melanoma genomic profiling, the mutational landscape of primary mucosal melanomas (PMM) remains unclear. Forty-six PMMs underwent targeted exome sequencing of 111 cancer-associated genes. Seventy-six somatic nonsynonymous mutations in 42 genes were observed, and recurrent mutations were noted on eight genes, including TP53 (13%), NRAS (13%), SNX31 (9%), NF1 (9%), KIT (7%) and APC (7%). Mitogen-activated protein kinase (MAPK; 37%), cell cycle (20%) and phosphatidylinositol 3-kinase (PI3K)-mTOR (15%) pathways were frequently mutated...
January 16, 2017: Oncogene
https://www.readbyqxmd.com/read/28070831/the-prolyl-oligopeptidase-inhibitor-suam-14746-attenuates-the-proliferation-of-human-breast-cancer-cell-lines-in-vitro
#2
Satoshi Tanaka, Kanayo Suzuki, Minoru Sakaguchi
BACKGROUND: Prolyl oligopeptidase (POP, EC 3.4.1.26) is a serine peptidase that hydrolyzes post-proline peptide bonds in peptides that are <30 amino acids in length. We previously reported that POP inhibition suppressed the growth of NB-1 human neuroblastomas cells and KATO III human gastric cancer cells. POP activity is commonly elevated in many cancers, which includes breast cancer. However, the effect of POP inhibition as a candidate breast cancer therapy is unknown. METHODS: The effects of POP inhibition and knockdown on the proliferation of cultured human estrogen receptor-positive (ER+) MCF7 and T47D, and ER-negative (ER-) MDA-MB-231 breast cancer cell lines and the MCF12A non-tumorigenic epithelial cell line were tested by analyzing their influence on cell proliferation (WST-1 assay), cell viability (trypan blue exclusion assay), and cell cycle arrest (cell cycle analysis, cell cycle regulator proteins expression)...
January 9, 2017: Breast Cancer: the Journal of the Japanese Breast Cancer Society
https://www.readbyqxmd.com/read/28062277/circ100284-via-mir-217-regulation-of-ezh2-is-involved-in-the-arsenite-accelerated-cell-cycle-of-human-keratinocytes-in-carcinogenesis
#3
Junchao Xue, Yang Liu, Fei Luo, Xiaolin Lu, Hui Xu, Xinlu Liu, Lu Lu, Qianlei Yang, Chao Chen, Weimin Fan, Qizhan Liu
Circular RNAs (circRNAs), a class of noncoding RNAs generated from pre-mRNAs, participate in regulation of genes. The mechanism for regulation, however, is unknown. Here, to determine if, in human keratinocyte (HaCaT) cells, circular RNAs are involved in arsenite-induced acceleration of the cell cycle, a circRNA microarray was performed to analyze the variability of circRNAs in arsenite-treated HaCaT (As-HaCaT) cells and in arsenite-transformed (T-HaCaT) cells in comparison to control HaCaT cells. Among the circRNAs up-regulated in both As-HaCaT cells and T-HaCaT cells, hsa:circRNA_100284 (circ100284) had the greatest increase and was chosen for further research...
January 3, 2017: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/28060055/genetic-counselling-and-high-penetrance-susceptibility-gene-analysis-reveal-the-novel-cdkn2a-p-d84v-c-251a-t-mutation-in-melanoma-prone-families-from-italy
#4
Riccardo G Borroni, Ausilia M Manganoni, Sara Grassi, Maurizia Grasso, Marta Diegoli, Carmela Giorgianni, Valentina Favalli, Laura Pavoni, Maddalena Cespa, Eloisa Arbustini
Genetic susceptibility to primary cutaneous melanoma (PCM) may account for up to 12% of PCMs, presenting as the familial atypical mole/multiple melanoma syndrome (FAMMM), an autosomal dominant condition with incomplete penetrance and variable expressivity, characterized by PCM in at least two relatives and/or more than one PCMs in the same patient. To identify individuals at high genetic risk of PCM, from 1 January 2012 to 31 December 2015, we offered genetic counselling and molecular analysis of the two high-penetrance FAMMM susceptibility genes, cyclin-dependent kinase inhibitor 2A (CDKN2A) and cyclin-dependent kinase 4 (CDK4), to 92 consecutive, unrelated patients with FAMMM...
January 4, 2017: Melanoma Research
https://www.readbyqxmd.com/read/28059068/cdk4-6-or-mapk-blockade-enhances-efficacy-of-egfr-inhibition-in-oesophageal-squamous-cell-carcinoma
#5
Jin Zhou, Zhong Wu, Gabrielle Wong, Eirini Pectasides, Ankur Nagaraja, Matthew Stachler, Haikuo Zhang, Ting Chen, Haisheng Zhang, Jie Bin Liu, Xinsen Xu, Ewa Sicinska, Francisco Sanchez-Vega, Anil K Rustgi, J Alan Diehl, Kwok-Kin Wong, Adam J Bass
Oesophageal squamous cell carcinoma is a deadly disease where systemic therapy has relied upon empiric chemotherapy despite the presence of genomic alterations pointing to candidate therapeutic targets, including recurrent amplification of the gene encoding receptor tyrosine kinase epidermal growth factor receptor (EGFR). Here, we demonstrate that EGFR-targeting small-molecule inhibitors have efficacy in EGFR-amplified oesophageal squamous cell carcinoma (ESCC), but may become quickly ineffective. Resistance can occur following the emergence of epithelial-mesenchymal transition and by reactivation of the mitogen-activated protein kinase (MAPK) pathway following EGFR blockade...
January 6, 2017: Nature Communications
https://www.readbyqxmd.com/read/28050067/palbociclib-a-breakthrough-in-breast-carcinoma-in-women
#6
REVIEW
Ajay Kumar Gupta, Sushil Sharma, Navdeep Dahiya, D B S Brashier
Breast cancer (BC) is the most common cancer and leading cause of death in women worldwide. Cellular proliferation, growth, and division are tightly controlled by the cell-cycle regulatory machinery. An important pathway is cyclin-dependent kinases (CDKs) which regulate cell cycle and thus control transcriptional processes. In human cancer, multiple CDK family members are commonly deregulated. The cyclin D-CDK4/6-retinoblastoma (RB) protein-INK4 axis is particularly affected in many solid tumors which leads to cancer cell proliferation...
December 2016: Medical Journal, Armed Forces India
https://www.readbyqxmd.com/read/28044938/development-of-selective-cyclin-dependent-kinase-4-inhibitors-for-antineoplastic-therapies
#7
Haixing Guan, Yongli Du, Weiwei Han, Jingkang Shen, Qunyi Li
Cyclin-Dependent Kinases 4 (CDK4) belongs to a family of serine-threonine protein kinase and plays key regulatory role in G1-phase of cell cycle progression. Compelling evidences have shown that targeting CDK4 pathway is an attractive proposition for tumor therapy. Recent progresses of selective small molecule CDK4 inhibitors in cancer therapy have endorsed the field to be interested and attractive. In this review, we will discuss the recent developments of CDK4 inhibitors on several aspects such as the structure of CDK4, the working mechanism of CDK4 inhibitors, the structure activity relationships (SARs) of the selective CDK4 inhibitors and the latest developments of the selective CDK4 inhibitors in clinical trials...
January 2, 2017: Anti-cancer Agents in Medicinal Chemistry
https://www.readbyqxmd.com/read/28042706/do-cdk4-6-inhibitors-have-potential-as-targeted-therapeutics-for-squamous-cell-cancers
#8
Nene N Kalu, Faye M Johnson
Introduction Dysregulation of cell cycle progression has an established link to neoplasia and cancer progression. Components of the cyclin D-CDK4/6-INK4-Rb pathway are frequently altered in squamous cell carcinomas (SCCs) by diverse mechanisms, including viral oncogene-induced degradation, mutation, deletion, and amplification. Activation of the CDK4/6 pathway may predict response to CDK4/6 inhibitors and provide clinical biomarkers. Recently, the CDK4/6 inhibitor palbociclib showed clinical efficacy in combination with cetuximab in HNSCC patients...
January 1, 2017: Expert Opinion on Investigational Drugs
https://www.readbyqxmd.com/read/28042144/novel-bet-protein-proteolysis-targeting-chimera-bet-protac-exerts-superior-lethal-activity-than-bromodomain-inhibitor-beti-against-post-myeloproliferative-neoplasm-mpn-secondary-s-aml-cells
#9
D T Saenz, W Fiskus, Y Qian, T Manshouri, K Rajapakshe, K Raina, K G Coleman, A P Crew, A Shen, C P Mill, B Sun, P Qiu, T M Kadia, N Pemmaraju, C DiNardo, M-S Kim, A J Nowak, C Coarfa, C M Crews, S Verstovsek, K N Bhalla
The PROTAC (proteolysis-targeting chimera) ARV-825 recruits bromodomain and extraterminal (BET) proteins to the E3 ubiquitin ligase cereblon, leading to degradation of BET proteins, including BRD4. Whereas the BET-protein inhibitor (BETi) OTX015 caused accumulation of BRD4, treatment with equimolar concentrations of ARV-825 caused sustained and profound depletion (>90%) of BRD4 and induced significantly more apoptosis in cultured and patient-derived (PD) CD34+ post-MPN sAML cells, while relatively sparing the CD34+ normal hematopoietic progenitor cells...
January 2, 2017: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
https://www.readbyqxmd.com/read/28039467/targeting-cancer-stem-cell-propagation-with-palbociclib-a-cdk4-6-inhibitor-telomerase-drives-tumor-cell-heterogeneity
#10
Gloria Bonuccelli, Maria Peiris-Pages, Bela Ozsvari, Ubaldo E Martinez-Outschoorn, Federica Sotgia, Michael P Lisanti
In this report, we systematically examined the role of telomerase activity in lung and ovarian cancer stem cell (CSC) propagation. For this purpose, we indirectly gauged telomerase activity, by linking the hTERT-promoter to eGFP. Using lung (A549) and ovarian (SKOV3) cancer cells, transduced with the hTERT-GFP reporter, we then employed GFP-expression levels to fractionate these cell lines into GFP-high and GFP-low populations. We functionally compared the phenotype of these GFP-high and GFP-low populations...
December 25, 2016: Oncotarget
https://www.readbyqxmd.com/read/28039358/stromal-senescence-by-prolonged-cdk4-6-inhibition-potentiates-tumor-growth
#11
Xiangnan Guan, Kyle M LaPak, Rebecca C Hennessey, Christina Y Yu, Reena Shakya, Jianying Zhang, Christin E Burd
: Senescent cells within the tumor microenvironment (TME) adopt a pro-inflammatory, senescence-associated secretory phenotype (SASP) that promotes cancer initiation, progression and therapeutic resistance. Here, exposure to Palbociclib (PD-0332991), a CDK4/6 inhibitor, induces senescence and a robust SASP in normal fibroblasts. Senescence caused by prolonged CDK4/6 inhibition is DNA damage-independent and associated with Mdm2 downregulation, whereas the SASP elicited by these cells is largely reliant upon NF-kappaB activation...
December 30, 2016: Molecular Cancer Research: MCR
https://www.readbyqxmd.com/read/28009720/roscovitine-protects-from-arterial-injury-by-regulating-the-expressions-of-c-jun-and-p27-and-inhibiting-vsmc-proliferation
#12
Yu Liu, Yun-Feng Li, Hong Chang, Jing-Shan Zhao, Jian-Ming Hou, Kun Yu, Jia-Huan Sun, Hong Wang, Ai-Ying Li
PURPOSE: Roscovitine (Rosc) is a selective inhibitor of cyclin-dependent kinases (CDKs) and a promising therapy for various cancers. However, limited information is available on the biological significance of Rosc in vascular smooth muscle cells (VSMCs), the cell type critical for the development of proliferative vascular diseases. In this study, we address the effects of Rosc in regulating VSMC proliferation, both in vitro and in vivo, exploring the underlying molecular mechanisms. METHODS: The proliferations and cell-cycle distributions of in vitro cultured VSMCs, as well as several other cancer cell lines, were examined by cell-counting assay and flow cytometry, respectively...
December 17, 2016: Journal of Cardiovascular Pharmacology
https://www.readbyqxmd.com/read/27986745/dual-alk-and-cdk4-6-inhibition-demonstrates-on-target-synergy-against-neuroblastoma
#13
Andrew Wood, Kateryna Krytska, Hannah T Ryles, Nicole R Infarinato, Renata Sano, Theodore D Hansel, Lori S Hart, Frederick King, Timothy R Smith, Edward Ainscow, Kathryn B Grandinetti, Tove Tuntland, Sunkyu Kim, Giordano Caponigro, You-Qun He, Shiva Krupa, Nanxin Li, Jennifer Harris, Yael P Mosse
PURPOSE: Anaplastic Lymphoma Kinase (ALK) is the most frequently mutated oncogene in the pediatric cancer neuroblastoma. We performed an in vitro screen for synergistic drug combinations that target neuroblastomas with mutations in ALK to determine if drug combinations could enhance anti-tumor efficacy. EXPERIMENTAL DESIGN: We screened combinations of eight molecularly targeted agents against seventeen comprehensively characterized human neuroblastoma-derived cell lines...
December 16, 2016: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/27986713/abemaciclib-shows-promise-for-early-breast-cancer
#14
(no author information available yet)
Treatment with the CDK4/6 inhibitor abemaciclib, alone or in combination with endocrine therapy, significantly lowered expression of the protein Ki67-a key marker of cell proliferation-in women with hormone receptor-positive, HER2-negative breast cancer. The findings from the phase II neoMONARCH trial suggest that CDK4/6 inhibition may be effective for neoadjuvant treatment of early breast cancer.
December 16, 2016: Cancer Discovery
https://www.readbyqxmd.com/read/27960642/the-role-of-cdkn2a-b-deletions-in-pediatric-acute-lymphoblastic-leukemia
#15
P Carrasco Salas, L Fernández, M Vela, D Bueno, B González, J Valentín, P Lapunzina, A Pérez-Martínez
The CDKN2A/B genes in the 9p21 chromosomal region are frequently involved in human cancer, including pediatric acute lymphoblastic leukemia (ALL). These genes encode 3 proteins that belong to the RB1 and TP53 pathways and act as tumor suppressors by regulating the G1/S checkpoint of the cell cycle. The prognostic value of deletions in the CDKN2A/B locus in ALL is controversial in part due to the limitations of the methodologies used. Further studies with advanced technologies are needed for elucidation. Future studies would also highlight whether CDK4/CDK6 selective inhibitors might be useful therapies for children with these genetic aberrations...
October 2016: Pediatric Hematology and Oncology
https://www.readbyqxmd.com/read/27959407/low-dose-irradiation-promotes-proliferation-of-the-human-breast-cancer-mda-mb-231-cells-through-accumulation-of-mutant-p53
#16
Si-Jie Li, Xin-Yue Liang, Hai-Jun Li, Wei Li, Lei Zhou, Hua-Qiu Chen, Song-Gen Ye, De-Hai Yu, Jiu-Wei Cui
Low-dose irradiation (LDIR) has been proven to have differential biological effects on normal mammalian somatic cells and cancer cells. Our previous study showed that p53 gene status is a critical factor regulating the effect of LDIR on cancer cells. We investigated the effect of LDIR on the breast cancer cell line MDA-MB-231 that harbors a mutant p53 gene, and the normal breast fibroblast cell line Hs 578Bst. In the present study, we showed that 150 mGy LDIR pormoted growth of MDA-MB-231 cells but not Hs 578Bst cells...
January 2017: International Journal of Oncology
https://www.readbyqxmd.com/read/27959342/ailanthone-targets-p23-to-overcome-mdv3100-resistance-in-castration-resistant-prostate-cancer
#17
Yundong He, Shihong Peng, Jinhua Wang, Huang Chen, Xiaonan Cong, Ang Chen, Meichun Hu, Min Qin, Haigang Wu, Shuman Gao, Liguo Wang, Xin Wang, Zhengfang Yi, Mingyao Liu
Androgen receptor (AR) antagonist MDV3100 is the first therapeutic approach in treating castration-resistant prostate cancer (CRPC), but tumours frequently become drug resistant via multiple mechanisms including AR amplification and mutation. Here we identify the small molecule Ailanthone (AIL) as a potent inhibitor of both full-length AR (AR-FL) and constitutively active truncated AR splice variants (AR-Vs). AIL binds to the co-chaperone protein p23 and prevents AR's interaction with HSP90, thus resulting in the disruption of the AR-chaperone complex followed by ubiquitin/proteasome-mediated degradation of AR as well as other p23 clients including AKT and Cdk4, and downregulates AR and its target genes in PCa cell lines and orthotopic animal tumours...
December 13, 2016: Nature Communications
https://www.readbyqxmd.com/read/27942664/phenolics-extracted-from-tartary-fagopyrum-tartaricum-l-gaerth-buckwheat-bran-exhibit-antioxidant-activity-and-an-antiproliferative-effect-on-human-breast-cancer-mda-mb-231-cells-through-the-p38-map-kinase-pathway
#18
Fuhua Li, Xiaoli Zhang, Yao Li, Keke Lu, Ran Yin, Jian Ming
Phenolics extracted from tartary buckwheat (Fagopyrum tartaricum L. Gaerth) bran were analyzed quantitatively and qualitatively. The bioactivity of the phenolic extracts was evaluated, such as the antioxidant activity, and the inhibition capacity on the growth of cancer cells. The molecular mechanism for the inhibitive effect on cancer cells was explored. Results indicated that tartary buckwheat bran phenolics mainly exist in a free form, and free phenolics were twice as abundant as bound phenolics. Free caffeic acid (119...
December 12, 2016: Food & Function
https://www.readbyqxmd.com/read/27939057/advances-in-the-treatment-of-advanced-oestrogen-receptor-positive-breast-cancer
#19
REVIEW
Nicholas C Turner, Patrick Neven, Sibylle Loibl, Fabrice Andre
Oestrogen-receptor-positive breast cancer is the most common subtype of breast cancer. Endocrine therapies that target the dependence of this subtype on the oestrogen receptor have substantial activity, yet the development of resistance to therapy is inevitable in advanced cancer. Major progress has been made in identifying the drivers of oestrogen-receptor-positive breast cancer and the mechanisms of resistance to endocrine therapy. This progress has translated into major advances in the treatment of advanced breast cancer, with several targeted therapies that enhance the efficacy of endocrine therapy; inhibitors of mTOR and inhibitors of the cyclin-dependent kinases CDK4 and CDK6 substantially improve progression-free survival...
December 6, 2016: Lancet
https://www.readbyqxmd.com/read/27923036/cotargeting-of-cyp-19-aromatase-and-emerging-pivotal-signalling-pathways-in-metastatic-breast-cancer
#20
REVIEW
Stine Daldorff, Randi Margit Ruud Mathiesen, Olav Erich Yri, Hilde Presterud Ødegård, Jürgen Geisler
Aromatase inhibition is one of the cornerstones of modern endocrine therapy of oestrogen receptor-positive (ER+) metastatic breast cancer (MBC). The nonsteroidal aromatase inhibitors anastrozole and letrozole, as well as the steroidal aromatase inactivator exemestane, are the preferred drugs and established worldwide in all clinical phases of the disease. However, although many patients suffering from MBC experience an initial stabilisation of their metastatic burden, drug resistance and disease progression occur frequently, following in general only a few months on treatment...
January 3, 2017: British Journal of Cancer
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