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CDK4/6 AND cancer

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https://www.readbyqxmd.com/read/28627629/reducing-autophagy-and-inducing-g1-phase-arrest-by-aloperine-enhances-radio-sensitivity-in-lung-cancer-cells
#1
Zhijie Xu, Yuanliang Yan, Shuangshuang Zeng, Long Qian, Shuang Dai, Lingfang Xiao, Lin Wang, Xue Yang, Yi Xiao, Zhicheng Gong
Aloperine (ALO), an isolated alkaloid from the leaves of Sophora alopecuroides (S. alopecuroides), has been suggested to exhibit anti-inflammatory and antitumor properties, and has been traditionally used to treat various diseases, including cancers. However, little is known about the effects of ALO on the radio-sensitivity of lung cancer cells. In the present study, we confirmed that agent ALO inhibits cell growth, promotes cell aopotosis and induces G1 phase arrest and consequently enhanced the radio-sensitivity in radio-resistant lung cancer cells A549/IR...
June 19, 2017: Oncology Reports
https://www.readbyqxmd.com/read/28626036/treating-er-breast-cancer-with-cdk4-6-inhibitors
#2
(no author information available yet)
Data from the MONARCH2, PALOMA-1, and TREnd trials strongly support using CDK4/6 inhibitors alongside standard endocrine therapy for advanced ER-positive breast cancer. Including these targeted agents not only improves progression-free survival but may reverse acquired resistance to hormone treatment.
June 16, 2017: Cancer Discovery
https://www.readbyqxmd.com/read/28620137/biological-specificity-of-cdk4-6-inhibitors-dose-response-relationship-in-vivo-signaling-and-composite-response-signature
#3
Erik S Knudsen, Jack Hutcheson, Paris Vail, Agnieszka K Witkiewicz
Recently developed potent and selective CDK4/6 inhibitors fall into two classes based on structure and toxicity profiles in clinical studies. One class, exemplified by palbociclib and ribociclib, exhibits neutropenia as a dose-limiting toxicity and requires discontinuous dosing. In contrast, the structurally distinct CDK4/6 inhibitor abemaciclib is dosed continuously, and has diarrhea and fatigue as dose-limiting toxicities. In preclinical models, palbociclib has been extensively studied and induces cell cycle inhibition in an RB-dependent manner...
June 10, 2017: Oncotarget
https://www.readbyqxmd.com/read/28607489/the-metabolic-function-of-cyclin-d3-cdk6-kinase-in-cancer-cell-survival
#4
Haizhen Wang, Brandon N Nicolay, Joel M Chick, Xueliang Gao, Yan Geng, Hong Ren, Hui Gao, Guizhi Yang, Juliet A Williams, Jan M Suski, Mark A Keibler, Ewa Sicinska, Ulrike Gerdemann, W Nicholas Haining, Thomas M Roberts, Kornelia Polyak, Steven P Gygi, Nicholas J Dyson, Piotr Sicinski
D-type cyclins (D1, D2 and D3) and their associated cyclin-dependent kinases (CDK4 and CDK6) are components of the core cell cycle machinery that drives cell proliferation. Inhibitors of CDK4 and CDK6 are currently being tested in clinical trials for patients with several cancer types, with promising results. Here, using human cancer cells and patient-derived xenografts in mice, we show that the cyclin D3-CDK6 kinase phosphorylates and inhibits the catalytic activity of two key enzymes in the glycolytic pathway, 6-phosphofructokinase and pyruvate kinase M2...
June 15, 2017: Nature
https://www.readbyqxmd.com/read/28606920/single-cell-dynamics-determines-response-to-cdk4-6-inhibition-in-triple-negative-breast-cancer
#5
Uzma Asghar, Alexis R Barr, Ros Cutts, Matthew Beaney, Irina S Babina, Deepak Sampath, Jennifer Giltnane, Jennifer A Lacap, Lisa Crocker, Amy Young, Alex Pearson, Maria Teresa Herrera-Abreu, Chris Bakal, Nicholas C Turner
Purpose: Triple negative breast cancer (TNBC) is a heterogeneous subgroup of breast cancer that is associated with a poor prognosis. We evaluated the activity of CDK4/6 inhibitors across the TNBC subtypes, and investigated mechanisms of sensitivity. <p>Experimental design: A panel of cell lines representative of TNBC were tested for in vitro and in vivo sensitivity to CDK4/6 inhibition. A fluorescent CDK2 activity reporter was used for single cell analysis in conjunction with time-lapse imaging.</p> <p>Results: The luminal androgen receptor (LAR) subtype of TNBC was highly sensitive to CDK4/6 inhibition both in vitro [p<0...
June 12, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/28604107/accelerating-drug-development-for-neuroblastoma-new-drug-development-strategy-an-innovative-therapies-for-children-with-cancer-european-network-for-cancer-research-in-children-and-adolescents-and-international-society-of-paediatric-oncology-europe-neuroblastoma
#6
Lucas Moreno, Hubert Caron, Birgit Geoerger, Angelika Eggert, Gudrun Schleiermacher, Penelope Brock, Dominique Valteau-Couanet, Louis Chesler, Johannes H Schulte, Katleen De Preter, Jan Molenaar, Alexander Schramm, Martin Eilers, Tom Van Maerken, John Inge Johnsen, Michelle Garrett, Sally L George, Deborah A Tweddle, Per Kogner, Frank Berthold, Jan Koster, Giuseppe Barone, Elizabeth R Tucker, Lynley Marshall, Ralf Herold, Jaroslav Sterba, Koen Norga, Gilles Vassal, Andrew Dj Pearson
Neuroblastoma, the commonest paediatric extra-cranial tumour, remains a leading cause of death from cancer in children. There is an urgent need to develop new drugs to improve cure rates and reduce long-term toxicity and to incorporate molecularly targeted therapies into treatment. Many potential drugs are becoming available, but have to be prioritised for clinical trials due to the relatively small numbers of patients. Areas covered: The current drug development model has been slow, associated with significant attrition, and few new drugs have been developed for neuroblastoma...
June 12, 2017: Expert Opinion on Drug Discovery
https://www.readbyqxmd.com/read/28585619/-palbociclib-combinations-as-new-therapeutic-strategies-in-the-treatment-of-hr-her2-advanced-breast-cancer
#7
Katalin Boér
Until recently, the only endocrine agents used to treat HR+/HER2- advanced breast cancers were tamoxifen, aromatase inhibitors and fulvestrant, although a substantial proportion of patients relapse on these standard therapies. Intensive research has been conducted to develop new strategies to overcome endocrine resistance and to enhance the efficacy of endocrine treatments by combining hormone therapy with other targeted treatment approaches. The development of selective CDK4/6 inhibitors and the introduction of palbociclib, the first molecule in this class in clinical practice, represent an important step in the treatment of HR+ advanced breast cancer...
June 6, 2017: Magyar Onkologia
https://www.readbyqxmd.com/read/28580868/cell-cycle-therapeutics-come-of-age
#8
Matthew Ingham, Gary K Schwartz
The ability to sustain unscheduled proliferation is a hallmark of cancer. The normal process of cell division occurs via the cell cycle, a series of highly regulated steps that are orchestrated at the molecular level by specific cyclins that act in association with cyclin-dependent kinases (CDKs). Cyclin D and CDK4/6 play a key role in cell-cycle progression by phosphorylating and inactivating the retinoblastoma protein, a tumor suppressor that restrains G1- to S-phase progression. The first-generation CDK inhibitors demonstrated broad activity upon several CDKs, which likely explains their considerable toxicities and limited efficacy...
June 3, 2017: Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology
https://www.readbyqxmd.com/read/28566333/cdk4-phosphorylation-status-and-a-linked-gene-expression-profile-predict-sensitivity-to-palbociclib
#9
Eric Raspé, Katia Coulonval, Jaime M Pita, Sabine Paternot, Françoise Rothé, Laure Twyffels, Sylvain Brohée, Ligia Craciun, Denis Larsimont, Véronique Kruys, Flavienne Sandras, Isabelle Salmon, Steven Van Laere, Martine Piccart, Michail Ignatiadis, Christos Sotiriou, Pierre P Roger
Cyclin D-CDK4/6 are the first CDK complexes to be activated in the G1 phase in response to oncogenic pathways. The specific CDK4/6 inhibitor PD0332991 (palbociclib) was recently approved by the FDA and EMA for treatment of advanced ER-positive breast tumors. Unfortunately, no reliable predictive tools are available for identifying potentially responsive or insensitive tumors. We had shown that the activating T172 phosphorylation of CDK4 is the central rate-limiting event that initiates the cell cycle decision and signals the presence of active CDK4...
May 31, 2017: EMBO Molecular Medicine
https://www.readbyqxmd.com/read/28560460/synthetic-lethal-interaction-of-cdk-inhibition-and-autophagy-inhibition-in-human-solid-cancer-cell-lines
#10
Yoshinari Okada, Shunsuke Kato, Yasuhiro Sakamoto, Takayuki Oishi, Chikashi Ishioka
Cell cycle control is a promising target in cancer treatments, and some small-molecule cyclin-dependent kinase (CDK) inhibitors have exhibited clinical effectiveness. However, no biomarkers predictive of efficacy have been developed. Recent studies have revealed that CDK inhibitor (CKI) proteins, such as p27 and p16, also induced cytoprotective autophagy in cancer cells. However, it is unclear whether small-molecule CKIs also induce autophagy in solid tumors, as induced autophagy promotes cancer cell survival...
May 30, 2017: Oncology Reports
https://www.readbyqxmd.com/read/28560411/cpg-methylation-patterns-are-associated-with-gene-expression-variation-in-osteosarcoma
#11
Qiang Wang
Osteosarcoma is a common malignant tumor in childhood and adolescence (nearly 5% of all cases of cancer in children), as well as a type of tumor with poor prognosis. However, the pathogenesis and molecular mechanisms of osteosarcoma remains to be elucidated. The aim of the current study was to determine the association between methylation and gene expression changes in osteosarcoma cell line. Microarray data were obtained from the Gene Expression Omnibus database (GSE36004). Genome‑wide methylation status was determined in 19 different osteosarcoma cell lines and 6 normal controls...
July 2017: Molecular Medicine Reports
https://www.readbyqxmd.com/read/28559771/cdk4-6-inhibitors-in-the-treatment-of-metastatic-breast-cancer
#12
Johannes Ettl, Jens Huober, Diana Lüftner, Frederik Marmé, Rachel Würstlein
No abstract text is available yet for this article.
May 2017: Breast Care
https://www.readbyqxmd.com/read/28537004/mek-inhibitors-in-the-treatment-of-metastatic-melanoma-and-solid-tumors
#13
REVIEW
Antonio M Grimaldi, Ester Simeone, Lucia Festino, Vito Vanella, Martina Strudel, Paolo A Ascierto
The mitogen-activated protein kinase (MAPK) cascade is an intracellular signaling pathway involved in the regulation of cellular proliferation and the survival of tumor cells. Several different mutations, involving BRAF or NRAS, exert an oncogenic effect by activating the MAPK pathway, resulting in an increase in cellular proliferation. These mutations have become targets for new therapeutic strategies in melanoma and other cancers. Selective MEK inhibitors have the ability to inhibit growth and induce cell death in BRAF- and NRAS-mutant melanoma cell lines...
May 23, 2017: American Journal of Clinical Dermatology
https://www.readbyqxmd.com/read/28533223/monarch-1-a-phase-2-study-of-abemaciclib-a-cdk4-and-cdk6-inhibitor-as-a-single-agent-in-patients-with-refractory-hr-her2-metastatic-breast-cancer
#14
Maura N Dickler, Sara Tolaney, Hope S Rugo, Javier Cortés, Veronique Dieras, Debra A Patt, Hans Wildiers, Clifford A Hudis, Joyce A O'Shaughnessy, Esther Zamora, Denise Yardley, Martin Frenzel, Andrew G Koustenis, José Baselga
<br />The phase 2 MONARCH 1 study was designed to evaluate the single-agent activity and adverse event (AE) profile of abemaciclib, a selective inhibitor of CDK4 and CDK6, in women with refractory hormone receptor positive (HR+), HER2- metastatic breast cancer (MBC). <br /><br />Experimental Design: <br />MONARCH 1 was a phase 2 single arm open-label study. Women with HR+/HER2- MBC who had progressed on or after prior endocrine therapy and had 1 or 2 chemotherapy regimens in the metastatic setting were eligible...
May 22, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/28530853/designing-clinical-trials-that-accept-new-arms-an-example-in-metastatic-breast-cancer
#15
Steffen Ventz, Brian M Alexander, Giovanni Parmigiani, Richard D Gelber, Lorenzo Trippa
Purpose The majority of randomized oncology trials are two-arm studies that test the efficacy of new therapies against a standard of care, thereby assigning a large proportion of patients to nonexperimental therapies. In contrast, multiarm studies efficiently share a common control arm while evaluating multiple experimental therapies. A major bottleneck for traditional multiarm trials is the requirement that all therapies-often drugs from different companies-have to be available at the same time when the trial starts...
May 22, 2017: Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology
https://www.readbyqxmd.com/read/28529550/hormonoresistance-in-advanced-breast-cancer-a-new-revolution-in-endocrine-therapy
#16
REVIEW
Paule Augereau, Anne Patsouris, Emmanuelle Bourbouloux, Carole Gourmelon, Sophie Abadie Lacourtoisie, Dominique Berton Rigaud, Patrick Soulié, Jean Sebastien Frenel, Mario Campone
Endocrine therapy is the mainstay of treatment of estrogen-receptor-positive (ER+) breast cancer with an overall survival benefit. However, some adaptive mechanisms in the tumor emerge leading to the development of a resistance to this therapy. A better characterization of this process is needed to overcome this resistance and to develop new tailored therapies. Mechanisms of resistance to hormone therapy result in activation of transduction signal pathways, including the cell cycle regulation with cyclin D/CDK4/6/Rb pathway...
May 2017: Therapeutic Advances in Medical Oncology
https://www.readbyqxmd.com/read/28526299/mir-200a-regulates-cdk4-6-inhibitor-effect-by-targeting-cdk6-in-metastatic-melanoma
#17
Matias A Bustos, Shigeshi Ono, Diego M Marzese, Takashi Oyama, Yuuki Iida, Garrett Cheung, Nellie Nelson, Sandy C Hsu, Qiang Yu, Dave S B Hoon
Cyclin-dependent kinase (CDK) 4 and 6 pathway is frequently dysregulated in cutaneous melanoma. Recently, CDK4/6 inhibitors have shown promising clinical activity against several cancer types, including melanoma. Here, we demonstrate that miR-200a decreases CDK6 expression and thus reduces the response of CDK4/6 inhibitor in highly proliferative metastatic melanoma. Down-regulation of miR-200a expression in melanoma cells is associated with disease progression and a higher number of lymph node metastases. Furthermore, miR-200a expression is epigenetically modulated by both DNA methylation at the promoter region and chromatin accessibility of an upstream genomic region with enhancer activity...
May 16, 2017: Journal of Investigative Dermatology
https://www.readbyqxmd.com/read/28516152/cdk4-6-inhibitors-in-cancer-therapy-a%C3%A2-novel-treatement-strategy-for-bladder-cancer
#18
REVIEW
Qi Pan, Anuja Sathe, Peter C Black, Peter J Goebell, Ashish M Kamat, Bernd Schmitz-Draeger, Roman Nawroth
Patients with metastatic bladder cancer (mBC) treated with cisplatin-based chemotherapy have a limited median survival of only around 14 months [1]. Despite over 30 years of basic and clinical research, until recently no therapeutic options beyond cisplatin-based therapy had entered clinical routine and, at least in the US, none of the tested agents had been approved for second-line treatment. This has changed with the advent of immune checkpoint blockade, including especially PD-1/PD-L1 inhibitors. The high response rates of 24% over a 14...
April 27, 2017: Bladder Cancer
https://www.readbyqxmd.com/read/28515242/new-approaches-to-endocrine-therapy-for-breast-cancer
#19
William J Gradishar
The management of advanced hormone receptor-positive disease has evolved with the emergence of CDK4/6 inhibitors. Improvements in progression-free survival of approximately 10 months were noted in pivotal trials of palbociclib. Strong efficacy was also seen with ribociclib, which was recently approved by the FDA. In the adjuvant treatment setting of hormone receptor-positive disease, an important issue for consideration is the duration of endocrine therapy.
May 2017: Journal of the National Comprehensive Cancer Network: JNCCN
https://www.readbyqxmd.com/read/28513565/epidermal-growth-factor-receptor-cell-proliferation-signaling-pathways
#20
REVIEW
Ping Wee, Zhixiang Wang
The epidermal growth factor receptor (EGFR) is a receptor tyrosine kinase that is commonly upregulated in cancers such as in non-small-cell lung cancer, metastatic colorectal cancer, glioblastoma, head and neck cancer, pancreatic cancer, and breast cancer. Various mechanisms mediate the upregulation of EGFR activity, including common mutations and truncations to its extracellular domain, such as in the EGFRvIII truncations, as well as to its kinase domain, such as the L858R and T790M mutations, or the exon 19 truncation...
May 17, 2017: Cancers
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