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CDK4/6 AND cancer

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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/28067227/cdk4-6-dependent-activation-of-dub3-regulates-cancer-metastasis-through-snail1
#2
Tongzheng Liu, Jia Yu, Min Deng, Yujiao Yin, Haoxing Zhang, Kuntian Luo, Bo Qin, Yunhui Li, Chenming Wu, Tao Ren, Yang Han, Peng Yin, JungJin Kim, SeungBaek Lee, Jing Lin, Lizhi Zhang, Jun Zhang, Somaira Nowsheen, Liewei Wang, Judy Boughey, Matthew P Goetz, Jian Yuan, Zhenkun Lou
Tumour metastasis, the spread of cancer cells from the original tumour site followed by growth of secondary tumours at distant organs, is the primary cause of cancer-related deaths and remains poorly understood. Here we demonstrate that inhibition of CDK4/6 blocks breast tumour metastasis in the triple-negative breast cancer model, without affecting tumour growth. Mechanistically, we identify a deubiquitinase, DUB3, as a target of CDK4/6; CDK4/6-mediated activation of DUB3 is essential to deubiquitinate and stabilize SNAIL1, a key factor promoting epithelial-mesenchymal transition and breast cancer metastasis...
January 9, 2017: Nature Communications
https://www.readbyqxmd.com/read/28050067/palbociclib-a-breakthrough-in-breast-carcinoma-in-women
#3
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/28042706/do-cdk4-6-inhibitors-have-potential-as-targeted-therapeutics-for-squamous-cell-cancers
#4
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/28039467/targeting-cancer-stem-cell-propagation-with-palbociclib-a-cdk4-6-inhibitor-telomerase-drives-tumor-cell-heterogeneity
#5
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
#6
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/27986745/dual-alk-and-cdk4-6-inhibition-demonstrates-on-target-synergy-against-neuroblastoma
#7
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
#8
(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/27959954/protein-bound-polysaccharide-from-corbicula-fluminea-inhibits-cell-growth-in-mcf-7-and-mda-mb-231-human-breast-cancer-cells
#9
Ningbo Liao, Jianjun Zhong, Ronghua Zhang, Xingqian Ye, Yanjun Zhang, Wenjun Wang, Yuexia Wang, Shiguo Chen, Donghong Liu, Ruihai Liu
A novel protein-bound polysaccharide, CFPS-1, isolated from Corbicula fluminea, is composed predominantly of mannose (Man) and glucose (Glc) in a molar ratio of 3.1:12.7. The polysaccharide, with an average molecular weight of about 283 kDa, also contains 10.8% protein. Atomic force microscopy, high-performance liquid chromatography, Fourier transform infrared spectroscopy, gas chromatography/mass spectrometry, and nuclear magnetic resonance spectroscopy analyses revealed that CFPS-1 has a backbone of 1,6-linked and 1,4,6-linked-α-D-Glc, which is terminated with a 1-linked-α-D-Man residue at the O-4 position of 1,4,6-linked-α-D-Glc, in a molar ratio of 3:1:1...
2016: PloS One
https://www.readbyqxmd.com/read/27923036/cotargeting-of-cyp-19-aromatase-and-emerging-pivotal-signalling-pathways-in-metastatic-breast-cancer
#10
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
https://www.readbyqxmd.com/read/27883943/targeted-therapy-for-breast-cancer-and-molecular-mechanisms-of-resistance-to-treatment
#11
REVIEW
Guowei Gu, Derek Dustin, Suzanne Aw Fuqua
In recent years, clinical trials investigating new drugs and therapeutic combinations have led to promising advances in breast cancer therapy. Subtyping breast cancers into hormone receptor (HR) positive, epidermal growth factor receptor (HER2) positive, and triple negative breast cancer (TNBC) is currently the basis of diagnosing and treating this disease. In addition to endocrine and HER2-targeted therapies in their respective subtypes, evidence from recent preclinical studies have shown several targetable pathways that overcome resistance in the clinical setting...
December 2016: Current Opinion in Pharmacology
https://www.readbyqxmd.com/read/27864574/enhancing-endocrine-therapy-combination-strategies-for-the-treatment-of-postmenopausal-hormone-receptor-positive-her2-advanced-breast-cancer
#12
REVIEW
Kathleen I Pritchard, Stephen K Chia, Christine Simmons, Deanna McLeod, Alexander Paterson, Louise Provencher, Daniel Rayson
: : Breast cancer (BC) is the most common malignancy in women worldwide, with approximately two-thirds having hormone receptor (HR)-positive tumors. New endocrine therapy (ET) strategies include combining ET agents as well as adding inhibitors targeting growth factors, angiogenesis, the mechanistic target of rapamycin, phosphoinositide 3-kinase (PI3K), or cyclin-dependent kinase 4/6 to ET. Level 1 evidence supports use of fulvestrant plus anastrozole or palbociclib plus letrozole as first-line therapy for HR-positive, HER2-negative advanced BC with special consideration for the former in ET-naïve patients, as well as everolimus plus exemestane or palbociclib plus fulvestrant as second-line therapy with special consideration in select first-line patients...
November 18, 2016: Oncologist
https://www.readbyqxmd.com/read/27864221/cyclin-d-mediates-tolerance-of-genome-doubling-in-cancers-with-functional-p53
#13
A Crockford, L P Zalmas, E Grönroos, S M Dewhurst, N McGranahan, M E Cuomo, V Encheva, A P Snijders, J Begum, S Purewal, J Cerveira, H Patel, M J Renshaw, C Swanton
BACKGROUND: Aneuploidy and chromosomal instability (CIN) are common features of human malignancy that fuel genetic heterogeneity. Although tolerance to tetraploidisation, an intermediate state that further exacerbates CIN, is frequently mediated by TP53 dysfunction, we find that some genome-doubled tumours retain wild-type TP53 We sought to understand how tetraploid cells with a functional p53/p21-axis tolerate genome-doubling events. METHODS: We performed quantitative proteomics in a diploid/tetraploid pair within a system of multiple independently-derived TP53 wild-type tetraploid clones arising spontaneously from a diploid progenitor...
November 17, 2016: Annals of Oncology: Official Journal of the European Society for Medical Oncology
https://www.readbyqxmd.com/read/27855372/small-molecule-th-39-potentially-targets-hec1-nek2-interaction-and-exhibits-antitumor-efficacy-in-k562-cells-via-g0-g1-cell-cycle-arrest-and-apoptosis-induction
#14
Yongxia Zhu, Wei Wei, Tinghong Ye, Zhihao Liu, Li Liu, Yong Luo, Lidan Zhang, Chao Gao, Ningyu Wang, Luoting Yu
BACKGROUND: Cancer is still a major public health issue worldwide, and new therapeutics with anti-tumor activity are still urgently needed. METHODS: The anti-tumor activity of TH-39, which shows potent anti-proliferative activity against K562 cells with an IC50 of 0.78 µM, was investigated using immunoblot, co-immunoprecipitation, the MTT assay, and flow cytometry. RESULTS: Mechanistically, TH-39 may disrupt the interaction between Hec1 and Nek2 in K562 cells...
2016: Cellular Physiology and Biochemistry
https://www.readbyqxmd.com/read/27849562/palbociclib-pd-0332991-a-selective-cdk4-6-inhibitor-restricts-tumour-growth-in-preclinical-models-of-hepatocellular-carcinoma
#15
Julien Bollard, Verónica Miguela, Marina Ruiz de Galarreta, Anu Venkatesh, C Billie Bian, Mark P Roberto, Victoria Tovar, Daniela Sia, Pedro Molina-Sánchez, Christie B Nguyen, Shigeki Nakagawa, Josep M Llovet, Yujin Hoshida, Amaia Lujambio
OBJECTIVE: Advanced hepatocellular carcinoma (HCC) is a lethal malignancy with limited treatment options. Palbociclib, a well-tolerated and selective CDK4/6 inhibitor, has shown promising results in the treatment of retinoblastoma (RB1)-positive breast cancer. RB1 is rarely mutated in HCC, suggesting that palbociclib could potentially be used for HCC therapy. Here, we provide a comprehensive characterisation of the efficacy of palbociclib in multiple preclinical models of HCC. DESIGN: The effects of palbociclib on cell proliferation, cellular senescence and cell death were investigated in a panel of human liver cancer cell lines, in ex vivo human HCC samples, in a genetically engineered mouse model of liver cancer, and in human HCC xenografts in vivo...
November 14, 2016: Gut
https://www.readbyqxmd.com/read/27843622/review-of-hormone-based-treatments-in-postmenopausal-patients-with-advanced-breast-cancer-focusing-on-aromatase-inhibitors-and-fulvestrant
#16
REVIEW
Iben Kümler, Ann S Knoop, Christina A R Jessing, Bent Ejlertsen, Dorte L Nielsen
BACKGROUND: Endocrine therapy constitutes a central modality in the treatment of oestrogen receptor (ER)-positive advanced breast cancer. PURPOSE: To evaluate the evidence for endocrine treatment in postmenopausal patients with advanced breast cancer focusing on the aromatase inhibitors, letrozole, anastrozole, exemestane and fulvestrant. METHODS: A review was carried out using PubMed. Randomised phase II and III trials reporting on ≥100 patients were included...
2016: ESMO Open
https://www.readbyqxmd.com/read/27832204/expression-of-the-lncrna-maternally-expressed-gene-3-meg3-contributes-to-the-control-of-lung-cancer-cell-proliferation-by-the-rb-pathway
#17
Traci L Kruer, Susan M Dougherty, Lindsey Reynolds, Elizabeth Long, Tanya de Silva, William W Lockwood, Brian F Clem
Maternally expressed gene 3 (MEG3, mouse homolog Gtl2) encodes a long noncoding RNA (lncRNA) that is expressed in many normal tissues, but is suppressed in various cancer cell lines and tumors, suggesting it plays a functional role as a tumor suppressor. Hypermethylation has been shown to contribute to this loss of expression. We now demonstrate that MEG3 expression is regulated by the retinoblastoma protein (Rb) pathway and correlates with a change in cell proliferation. Microarray analysis of mouse embryonic fibroblasts (MEFs) isolated from mice with genetic deletion of all three Rb family members (TKO) revealed a significant silencing of Gtl2/MEG3 expression compared to WT MEFs, and re-expression of Gtl2/MEG3 caused decrease in cell proliferation and increased apoptosis...
2016: PloS One
https://www.readbyqxmd.com/read/27825114/pd-0332991-a-selective-cyclin-d-kinase-4-6-inhibitor-sensitizes-lung-cancer-cells-to-treatment-with-epidermal-growth-factor-receptor-tyrosine-kinase-inhibitors
#18
Minghui Liu, Song Xu, Yuli Wang, Ying Li, Yongwen Li, Hongbing Zhang, Hongyu Liu, Jun Chen
Acquired resistance to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) is a major challenge to targeted therapy for non-small cell lung cancer (NSCLC). We investigated whether a cyclin D kinase 4/6 (CDK4/6) inhibitor, PD 0332991, could reverse EGFR-TKI resistance in human lung cancer cells and explored the underlying mechanisms. We found that PD 0332991 potentiated gefitinib-induced growth inhibition in both EGFR-TKI-sensitive (PC-9) and EGFR-TKI-resistant (PC-9/AB2) cells by down-regulating proliferation and inducing apoptosis and G0/G1 cell cycle arrest...
November 4, 2016: Oncotarget
https://www.readbyqxmd.com/read/27816545/effect-of-abemaciclib-ly2835219-on-enhancement-of-chemotherapeutic-agents-in-abcb1-and-abcg2-overexpressing-cells-in-vitro-and-in-vivo
#19
Tong Wu, Zhen Chen, Kenneth K W To, Xiaona Fang, Fang Wang, Bin Cheng, Liwu Fu
Multidrug resistance (MDR) is the major obstacle of the success in cancer chemotherapy. The overexpression of ATP-binding cassette (ABC) transporters, particularly ABCB1 and ABCG2, play a significant role in mediating MDR by pumping anticancer drugs out of cancer cells. Abemaciclib (LY2835219) is an orally bioavailable CDK4/6 inhibitor under phase III clinical trials. Here, we found that LY2835219 remarkably enhanced the efficacy of chemotherapeutic drugs in ABCB1 or ABCG2 over-expressing cancer cells in vitro and in vivo...
January 15, 2017: Biochemical Pharmacology
https://www.readbyqxmd.com/read/27810861/ribociclib-lengthens-breast-cancer-survival
#20
(no author information available yet)
The combination of antiestrogen therapy and ribociclib, an investigational CDK4/6 inhibitor, led to improved outcomes in women with metastatic HR-positive, HER2-negative breast cancer, according to findings presented at a meeting of the European Society for Medical Oncology. The combination significantly increased progression-free survival compared with letrozole alone in a large phase III trial-data that could lead to FDA approval.
December 2016: Cancer Discovery
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