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Ribociclib

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https://www.readbyqxmd.com/read/28249908/kinome-wide-rna-interference-screen-reveals-a-role-for-pdk1-in-acquired-resistance-to-cdk4-6-inhibition-in-er-positive-breast-cancer
#1
Valerie M Jansen, Neil E Bhola, Joshua A Bauer, Luigi Formisano, Kyung-Min Lee, Katherine E Hutchinson, Agnieszka K Witkiewicz, Preston D Moore, Monica Valeria Estrada, Violeta Sanchez, Paula G Ericsson, Melinda Sanders, Paula R Pohlmann, Michael J Pishvaian, David A Riddle, Wenyi Wei, Teresa C Dugger, Erik Knudsen, Carlos L Arteaga
To discover mechanisms of resistance to CDK4/6 inhibitors, we used a kinome-wide siRNA screen to identify kinases that, when downregulated, promote sensitivity to ribociclib. We identified 3-phosphoinositide dependent protein kinase 1 (PDK1) as the top siRNA that sensitized ER+ MCF-7 cells to ribociclib. Pharmacological inhibition of PDK1 with GSK2334470 in combination with ribociclib or palbociclib, synergistically inhibited proliferation and increased apoptosis in a panel of ER+ breast cancer cell lines. Ribociclib-resistant MCF-7, T47D and HCC1428 cells, selected after chronic drug exposure, displayed increased levels of PDK1, P-RSK2, P-AKT and P-S6 compared to parental drug-sensitive cells...
March 1, 2017: Cancer Research
https://www.readbyqxmd.com/read/28226315/the-novel-cyclin-dependent-kinase-4-6-inhibitor-ribociclib-lee011-alone-and-in-dual-targeting-approaches-demonstrates-antitumoral-efficacy-in-neuroendocrine-tumors-in-vitro
#2
Elke Tatjana Aristizabal Prada, Svenja Noelting, Gerald Spoettl, Julian Maurer, Christoph Joseph Auernhammer
No abstract text is available yet for this article.
February 23, 2017: Neuroendocrinology
https://www.readbyqxmd.com/read/28197838/the-growing-role-of-cdk4-6-inhibitors-in-treating-hormone-receptor-positive-advanced-breast-cancer
#3
REVIEW
Ami N Shah, Massimo Cristofanilli
Single-agent endocrine therapy has been the standard therapeutic choice for the management of hormone receptor (HR)-positive, Her2-negative advanced breast cancer (ABC) for decades. However, the rapidly accumulating data regarding the biological role and safety of CDK4/6 inhibitors and the first-in-class approval of palbociclib have made these novel agents an essential component of treatment for HR-positive ABC. In the frontline setting, palbociclib in combination with endocrine therapy showed an improvement in progression-free survival (PFS) by 10 months to nearly 25 months when compared with endocrine therapy alone and a clinical benefit rate (CBR = stable disease >24 weeks + partial response + complete response) of 85%...
January 2017: Current Treatment Options in Oncology
https://www.readbyqxmd.com/read/28126188/-cell-cycle-inhibitors-in-endocrine-receptor-positive-breast-cancer
#4
Marie-Paule Sablin, Francesco Ricci, Delphine Loirat, Aude Jobard, Clémence Basse, Emanuela Romano, Christophe Le Tourneau, Véronique Dieras
Dysregulation of cellular cycle is a key component of carcinogenesis and its targeting represents an interesting approach. Recently, the development of selective inhibitors of the cycle targeting the cyclin-dependent kinases (CDK) 4 and 6 revived interest in this therapeutic class after the failure of pan-inhibitors. Palbociclib, ribociclib, and abemaciclib are the 3 drugs with the most advanced development. They demonstrated preclinical activity in luminal breast cancer models and are under clinical evaluation...
February 2017: Bulletin du Cancer
https://www.readbyqxmd.com/read/27986745/dual-alk-and-cdk4-6-inhibition-demonstrates-synergy-against-neuroblastoma
#5
Andrew C Wood, Kateryna Krytska, Hannah T Ryles, Nicole R Infarinato, Renata Sano, Theodore D Hansel, Lori S Hart, Frederick J King, Timothy R Smith, Edward Ainscow, Kathryn B Grandinetti, Tove Tuntland, Sunkyu Kim, Giordano Caponigro, You Qun He, Shiva Krupa, Nanxin Li, Jennifer L Harris, Yaël P Mossé
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 whether drug combinations could enhance antitumor efficacy.Experimental Design: We screened combinations of eight molecularly targeted agents against 17 comprehensively characterized human neuroblastoma-derived cell lines. We investigated the combination of ceritinib and ribociclib on in vitro proliferation, cell cycle, viability, caspase activation, and the cyclin D/CDK4/CDK6/RB and pALK signaling networks in cell lines with representative ALK status...
December 16, 2016: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/27810861/ribociclib-lengthens-breast-cancer-survival
#6
(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
https://www.readbyqxmd.com/read/27746106/ribociclib-in-hr-positive-her2-negative-breast-cancer
#7
Talha Khan Burki
No abstract text is available yet for this article.
October 13, 2016: Lancet Oncology
https://www.readbyqxmd.com/read/27729458/preclinical-therapeutic-synergy-of-mek1-2-and-cdk4-6-inhibition-in-neuroblastoma
#8
Lori S Hart, JulieAnn Rader, Pichai Raman, Vandana Batra, Michael R Russell, Matthew Tsang, Maria Gagliardi, Lucy Chen, Daniel Martinez, Yimei Li, Andrew Wood, Sunkyu Kim, Sudha Parasuraman, Scott Delach, Kristina A Cole, Shiva Krupa, Markus Boehm, Malte Peters, Giordano Caponigro, John M Maris
PURPOSE: Neuroblastoma is treated with aggressive multi-modal therapy, yet more than 50% of patients experience relapse. We recently showed that relapsed neuroblastomas frequently harbor mutations leading to hyperactivated ERK signaling and sensitivity to MEK inhibition therapy. Here we sought to define a synergistic therapeutic partner to potentiate MEK inhibition. EXPERIMENTAL DESIGN: We first surveyed 22 genetically annotated human neuroblastoma-derived cell lines (from 20 unique patients) for sensitivity to the MEK inhibitor binimetinib...
October 11, 2016: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/27717303/ribociclib-as-first-line-therapy-for-hr-positive-advanced-breast-cancer
#9
RANDOMIZED CONTROLLED TRIAL
Gabriel N Hortobagyi, Salomon M Stemmer, Howard A Burris, Yoon-Sim Yap, Gabe S Sonke, Shani Paluch-Shimon, Mario Campone, Kimberly L Blackwell, Fabrice André, Eric P Winer, Wolfgang Janni, Sunil Verma, Pierfranco Conte, Carlos L Arteaga, David A Cameron, Katarina Petrakova, Lowell L Hart, Cristian Villanueva, Arlene Chan, Erik Jakobsen, Arnd Nusch, Olga Burdaeva, Eva-Maria Grischke, Emilio Alba, Erik Wist, Norbert Marschner, Anne M Favret, Denise Yardley, Thomas Bachelot, Ling-Ming Tseng, Sibel Blau, Fengjuan Xuan, Farida Souami, Michelle Miller, Caroline Germa, Samit Hirawat, Joyce O'Shaughnessy
Background The inhibition of cyclin-dependent kinases 4 and 6 (CDK4/6) could potentially overcome or delay resistance to endocrine therapy in advanced breast cancer that is positive for hormone receptor (HR) and negative for human epidermal growth factor receptor 2 (HER2). Methods In this randomized, placebo-controlled, phase 3 trial, we evaluated the efficacy and safety of the selective CDK4/6 inhibitor ribociclib combined with letrozole for first-line treatment in 668 postmenopausal women with HR-positive, HER2-negative recurrent or metastatic breast cancer who had not received previous systemic therapy for advanced disease...
November 3, 2016: New England Journal of Medicine
https://www.readbyqxmd.com/read/27542767/a-phase-i-study-of-the-cyclin-dependent-kinase-4-6-inhibitor-ribociclib-lee011-in-patients-with-advanced-solid-tumors-and-lymphomas
#10
Jeffrey R Infante, Philippe A Cassier, John F Gerecitano, Petronella O Witteveen, Rashmi Chugh, Vincent Ribrag, Abhijit Chakraborty, Alessandro Matano, Jason R Dobson, Adam S Crystal, Sudha Parasuraman, Geoffrey I Shapiro
PURPOSE: Ribociclib (an oral, highly specific cyclin-dependent kinase 4/6 inhibitor) inhibits tumor growth in preclinical models with intact retinoblastoma protein (Rb(+)). This first-in-human study investigated the MTD, recommended dose for expansion (RDE), safety, preliminary activity, pharmacokinetics, and pharmacodynamics of ribociclib in patients with Rb(+) advanced solid tumors or lymphomas. EXPERIMENTAL DESIGN: Patients received escalating doses of ribociclib (3-weeks-on/1-week-off or continuous)...
December 1, 2016: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/27496135/spectrum-and-degree-of-cdk-drug-interactions-predicts-clinical-performance
#11
Ping Chen, Nathan V Lee, Wenyue Hu, Meirong Xu, Rose Ann Ferre, Hieu Lam, Simon Bergqvist, James Solowiej, Wade Diehl, You-Ai He, Xiu Yu, Asako Nagata, Todd VanArsdale, Brion W Murray
Therapeutically targeting aberrant intracellular kinase signaling is attractive from a biological perspective but drug development is often hindered by toxicities and inadequate efficacy. Predicting drug behaviors using cellular and animal models is confounded by redundant kinase activities, a lack of unique substrates, and cell-specific signaling networks. Cyclin-dependent kinase (CDK) drugs exemplify this phenomenon because they are reported to target common processes yet have distinct clinical activities...
October 2016: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/27493615/clinical-development-of-the-cdk4-6-inhibitors-ribociclib-and-abemaciclib-in-breast-cancer
#12
REVIEW
Romualdo Barroso-Sousa, Geoffrey I Shapiro, Sara M Tolaney
Clinical and preclinical data support a significant role for inhibitors of the cyclin-dependent kinases (CDKs) 4 and 6 in the treatment of patients with breast cancer. Recently, based on data showing improvement in progression-free survival, the use of palbociclib (Ibrance; Pfizer, Inc.) in combination with endocrine agents was approved to treat patients with hormone receptor-positive advanced disease. Importantly, 2 other CDK4/6 inhibitors, abemaciclib (LY2835219; Lilly) and ribociclib (LEE011; Novartis), are in the late stage of clinical development...
June 2016: Breast Care
https://www.readbyqxmd.com/read/27336726/ribociclib-plus-letrozole-in-early-breast-cancer-a-presurgical-window-of-opportunity-study
#13
RANDOMIZED CONTROLLED TRIAL
G Curigliano, P Gómez Pardo, F Meric-Bernstam, P Conte, M P Lolkema, J T Beck, A Bardia, M Martínez García, F Penault-Llorca, S Dhuria, Z Tang, N Solovieff, M Miller, E Di Tomaso, S A Hurvitz
OBJECTIVES: Cyclin D-cyclin-dependent kinase (CDK) 4/6-inhibitor of CDK4/6-retinoblastoma (Rb) pathway hyperactivation is associated with hormone receptor-positive (HR+) breast cancer (BC). This study assessed the biological activity of ribociclib (LEE011; CDK4/6 inhibitor) plus letrozole compared with single-agent letrozole in the presurgical setting. MATERIALS AND METHODS: Postmenopausal women (N = 14) with resectable, HR+, human epidermal growth factor receptor 2-negative (HER2-) early BC were randomized 1:1:1 to receive 2...
August 2016: Breast: Official Journal of the European Society of Mastology
https://www.readbyqxmd.com/read/27322766/cdk4-6-inhibitors-for-the-treatment-of-advanced-hormone-receptor-positive-breast-cancer-and-beyond-2016-update
#14
REVIEW
Ciara C O'Sullivan
INTRODUCTION: Breast cancer remains a major cause of morbidity and mortality worldwide. Given the central role of cyclin-dependent kinases in regulating cell division, there has been a longstanding interest in developing compounds which target the cyclin D1: CDK4/6 axis in breast cancer. The recent discovery of potent and selective CDK4/6 inhibitors (CDK4/6i) was an important breakthrough. AREAS COVERED: There are three CDK4/6i in clinical development (palbociclib, ribociclib and abemaciclib)...
August 2016: Expert Opinion on Pharmacotherapy
https://www.readbyqxmd.com/read/27220784/-combination-therapy-of-molecular-targeted-drugs-for-breast-cancer-their-potential-in-the-future
#15
Maiko Okano, Tohru Ohtake, Shigehira Saji
In breast cancer treatment, molecular-targeted drugs such as trastuzumab and lapatinib have been used for many y ears, and the benefits have been seen in many patients. The molecular-targeted drugs have mainly been used in combination with cytotoxic agents; however, combination therapies with 2 molecular-targeted drugs are currently being investigated. The combination therapy of 2 HER2 receptor antibodies, pertuzumab and trastuzumab, has tremendous benefit for HER2 positive metastatic breast cancer patients...
April 2016: Gan to Kagaku Ryoho. Cancer & Chemotherapy
https://www.readbyqxmd.com/read/27087139/cyclin-dependent-kinase-inhibitors-for-the-treatment-of-breast-cancer-past-present-and-future
#16
REVIEW
Adam J DiPippo, Neelam K Patel, Chad M Barnett
Treatment of metastatic breast cancer (MBC) that is resistant to endocrine therapy presents a significant clinical challenge. The well-known role of cell cycle dysregulation in these patients is partly mediated by cyclin-dependent kinase (CDK) activity. Specific cyclin and CDK complexes regulate cell cycle progression by managing the transition through the cell cycle, and inhibition of CDKs represents an important target for novel agents. First-generation CDK inhibitors (e.g., flavopiridol) were relatively nonselective and had an unacceptable toxicity profile in early trials...
2016: Pharmacotherapy
https://www.readbyqxmd.com/read/27030077/treating-cancer-with-selective-cdk4-6-inhibitors
#17
REVIEW
Ben O'Leary, Richard S Finn, Nicholas C Turner
Uncontrolled cellular proliferation, mediated by dysregulation of the cell-cycle machinery and activation of cyclin-dependent kinases (CDKs) to promote cell-cycle progression, lies at the heart of cancer as a pathological process. Clinical implementation of first-generation, nonselective CDK inhibitors, designed to inhibit this proliferation, was originally hampered by the high risk of toxicity and lack of efficacy noted with these agents. The emergence of a new generation of selective CDK4/6 inhibitors, including ribociclib, abemaciclib and palbociclib, has enabled tumour types in which CDK4/6 has a pivotal role in the G1-to-S-phase cell-cycle transition to be targeted with improved effectiveness, and fewer adverse effects...
July 2016: Nature Reviews. Clinical Oncology
https://www.readbyqxmd.com/read/27017286/targeting-cdk4-6-in-patients-with-cancer
#18
REVIEW
Erika Hamilton, Jeffrey R Infante
The cyclin D-cyclin dependent kinase (CDK) 4/6-inhibitor of CDK4 (INK4)-retinoblastoma (Rb) pathway controls cell cycle progression by regulating the G1-S checkpoint. Dysregulation of the cyclin D-CDK4/6-INK4-Rb pathway results in increased proliferation, and is frequently observed in many types of cancer. Pathway activation can occur through a variety of mechanisms, including gene amplification or rearrangement, loss of negative regulators, epigenetic alterations, and point mutations in key pathway components...
April 2016: Cancer Treatment Reviews
https://www.readbyqxmd.com/read/26995305/cyclin-dependent-protein-kinase-inhibitors-including-palbociclib-as-anticancer-drugs
#19
REVIEW
Robert Roskoski
Cyclins and cyclin-dependent protein kinases (CDKs) are important regulatory components that are required for cell cycle progression. The levels of the cell cycle CDKs are generally constant and their activities are controlled by cyclins, proteins whose levels oscillate during each cell cycle. Additional CDK family members were subsequently discovered that play significant roles in a wide range of activities including the control of gene transcription, metabolism, and neuronal function. In response to mitogenic stimuli, cells in the G1 phase of the cell cycle produce cyclins of the D type that activate CDK4/6...
May 2016: Pharmacological Research: the Official Journal of the Italian Pharmacological Society
https://www.readbyqxmd.com/read/26896604/targeting-the-cyclin-d-cyclin-dependent-kinase-cdk-4-6-retinoblastoma-pathway-with-selective-cdk-4-6-inhibitors-in-hormone-receptor-positive-breast-cancer-rationale-current-status-and-future-directions
#20
Laura Spring, Aditya Bardia, Shanu Modi
Dysregulation of the cyclin D-cyclin-dependent kinase (CDK) 4/6-INK4-retinoblastoma (Rb) pathway is an important contributor to endocrine therapy resistance. Recent clinical development of selective inhibitors of CDK4 and CDK6 kinases has led to renewed interest in cell cycle regulators, following experience with relatively non-selective pan-CDK inhibitors that often resulted in limited activity and poor safety profiles in the clinic. The highly selective oral CDK 4/6 inhibitors palbociclib (PD0332991), ribociclib (LEE011), and abemaciclib (LY2835219) are able to inhibit the proliferation of Rb-positive tumor cells and have demonstrated dose-dependent growth inhibition in ER+ breast cancer models...
January 2016: Discovery Medicine
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