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CDK4/6 AND cancer

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https://www.readbyqxmd.com/read/28927034/cyclin-d3-deficiency-inhibits-skin-tumor-development-but-does-not-affect-normal-keratinocyte-proliferation
#1
Sung Hyun Lee, Xian Wang, Sun Hye Kim, Yongbaek Kim, Marcelo L Rodriguez-Puebla
Rearrangement and amplification of the D-type cyclin genes have been reported in human cancer. Previous studies have demonstrated that Ras-mediated skin tumorigenesis depends on pathways that act through cyclin D1 and D2; however, the role of cyclin D3 remains unknown. The present study demonstrates that cyclin D3 ablation does not affect keratinocyte proliferation, but instead increases apoptosis levels in the bulge region of the hair follicle. Consequently, cyclin D3 ablation reduces skin papilloma development in a Ras-dependent carcinogenesis model...
September 2017: Oncology Letters
https://www.readbyqxmd.com/read/28923217/current-challenges-in-the-management-of-breast-cancer-brain-metastases
#2
REVIEW
Ciara C O'Sullivan, Nicole N Davarpanah, Jame Abraham, Susan E Bates
Approximately 50% of patients with advanced human epidermal growth factor 2 (HER2)-positive breast cancer and triple-negative breast cancer (TNBC) ultimately develop breast cancer brain metastases (BCBM), which are associated with significant morbidity and mortality. The advent of HER2-directed therapy resulted in greatly improved survival outcomes, but unfortunately at the price of an increased cumulative incidence of BCBM. We review challenges in the management of BCBM, and potential treatment strategies, including novel agents such as poly-adenosine diphosphate (ADP) ribose polymerase (PARP) inhibitors (olaparib, veliparib), cyclin-dependent kinase 4/6 (CDK4/6) inhibitors (palbociclib, abemaciclib), and taxane derivatives (eg, ANG1005 and TPI-287)...
April 2017: Seminars in Oncology
https://www.readbyqxmd.com/read/28922542/a-diphenyldiselenide-derivative-induces-autophagy-via-jnk-in-htb-54-lung-cancer-cells
#3
Marta Díaz, Roncesvalles González, Daniel Plano, Juan Antonio Palop, Carmen Sanmartín, Ignacio Encío
Symmetric aromatic diselenides are potential anticancer agents with strong cytotoxic activity. In this study, the in vitro anticancer activities of a novel series of diarylseleno derivatives from the diphenyldiselenide (DPDS) scaffold were evaluated. Most of the compounds exhibited high efficacy for inducing cytotoxicity against different human cancer cell lines. DPDS 2, the compound with the lowest mean GI50 value, induced both caspase-dependent apoptosis and arrest at the G0 /G1 phase in acute lymphoblastic leucemia CCRF-CEM cells...
September 18, 2017: Journal of Cellular and Molecular Medicine
https://www.readbyqxmd.com/read/28911822/structural-insights-of-cyclin-dependent-kinases-implications-in-design-of-selective-inhibitors
#4
REVIEW
Sourav Kalra, Gaurav Joshi, Anjana Munshi, Raj Kumar
There are around 20 Cyclin-dependent kinases (CDKs) known till date, and various research groups have reported their role in different types of cancer. The X-ray structures of some CDKs especially CDK2 was exploited in the past few years, and several inhibitors have been found, e.g., flavopiridol, indirubicin, roscovitine, etc., but due to the specificity issues of these inhibitors (binding to all CDKs), these were called as pan inhibitors. The revolutionary outcome of palbociclib in 2015 as CDK4/6 inhibitor added a new charm to the specific inhibitor design for CDKs...
September 4, 2017: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28903422/cdk4-6-inhibition-is-more-active-against-the-glioblastoma-proneural-subtype
#5
Ming Li, Aizhen Xiao, Desiree Floyd, Inan Olmez, Jeongwu Lee, Jakub Godlewski, Agnieszka Bronisz, Krishna P L Bhat, Erik P Sulman, Ichiro Nakano, Benjamin Purow
Glioblastoma (GBM) is the most common and lethal brain tumor. Gene expression profiling has classified GBM into distinct subtypes, including proneural, mesenchymal, and classical, and identifying therapeutic vulnerabilities of these subtypes is an extremely high priority. We leveraged The Cancer Genome Atlas (TCGA) data, in particular for microRNA expression, to seek druggable core pathways in GBM. The E2F1-regulated miR-17˜92 cluster and its analogs are shown to be highly expressed in proneural GBM and in GSC lines, suggesting the E2F cell cycle pathway might be a key driver in proneural GBM...
August 15, 2017: Oncotarget
https://www.readbyqxmd.com/read/28903138/improvement-of-genetic-testing-for-cutaneous-melanoma-in-countries-with-low-to-moderate-incidence-the-rule-of-2-vs-the-rule-of-3
#6
Juliette Delaunay, Ludovic Martin, Brigitte Bressac-de Paillerets, Gerard Duru, Olivier Ingster, Luc Thomas
Importance: Genetic testing for melanoma-prone mutation in France, a country with low to moderate incidence of melanoma, is proposed in cases with 2 invasive cutaneous melanomas and/or related cancers in the same patient, or in first- or second-degree relatives (rule of 2). In preclinical studies, these rules led to disclosure of mutation(s) in more than 10% of these families, the threshold widely accepted to justify genetic testing for cancers. Objective: To reconsider these criteria in a general population testing of patients...
September 13, 2017: JAMA Dermatology
https://www.readbyqxmd.com/read/28875723/ribociclib-for-post-menopausal-women-with-hr-her2-advanced-or-metastatic-breast-cancer
#7
Mark L Zangardi, Laura M Spring, Gayle C Blouin, Aditya Bardia
The introduction of CDK4/6 inhibitors, such as ribociclib, has changed the treatment landscape for post-menopausal women with HR+/HER2- advanced or metastatic breast cancer. As first-line treatment of HR+/HER2- MBC, the addition of a CDK4/6 inhibitor to an aromatase inhibitor improves progression-free survival compared to an aromatase inhibitor alone. Areas covered: In this drug profile, we review the current market for HR+/HER2- MBC, as well as the characteristics, mechanism, pharmacology, pharmacodynamics, pharmacokinetics, metabolism, clinical efficacy, toxicities, monitoring, and dosing modification of the CDK4/6 inhibitor ribociclib...
September 6, 2017: Expert Review of Clinical Pharmacology
https://www.readbyqxmd.com/read/28866094/palbociclib-a-selective-cdk4-6-inhibitor-enhances-the-effect-of-selumetinib-in-ras-driven-non-small-cell-lung-cancer
#8
Jianya Zhou, Shumeng Zhang, Xi Chen, Xianan Zheng, Yinan Yao, Guohua Lu, Jianying Zhou
KRAS is one of the most commonly mutated oncogenes in non-small cell lung cancer (NSCLC). Resistance to MEK inhibitor monotherapy develops through a variety of mechanisms. CDK4 was reported to have a synthetic lethal interaction with KRAS. In this study, we demonstrated the combination effects of the MEK inhibitor selumetinib and the CDK4/6 inhibitor palbociclib in RAS-driven NSCLC. In vitro, cell lines with CDKN2A mutations were insensitive to selumetinib. We used siRNA and pharmacologic inhibition of CDK4 and found that the combination of selumetinib and palbociclib synergistically inhibited RAS-driven NSCLC cases with CDKN2A mutations but not those with wild type CDKN2A...
September 1, 2017: Cancer Letters
https://www.readbyqxmd.com/read/28860801/nras-mutant-melanoma-current-challenges-and-future-prospect
#9
REVIEW
Eva Muñoz-Couselo, Ester Zamora Adelantado, Carolina Ortiz, Jesús Soberino García, José Perez-Garcia
Melanoma is one of the most common cutaneous cancers worldwide. Activating mutations in RAS oncogenes are found in a third of all human cancers and NRAS mutations are found in 15%-20% of melanomas. The NRAS-mutant subset of melanoma is more aggressive and associated with poorer outcomes, compared to non-NRAS-mutant melanoma. Although immune checkpoint inhibitors and targeted therapies for BRAF-mutant melanoma are transforming the treatment of metastatic melanoma, the ideal treatment for NRAS-mutant melanoma remains unknown...
2017: OncoTargets and Therapy
https://www.readbyqxmd.com/read/28856074/utilizing-tumor-and-plasma-liquid-biopsy-in-treatment-decision-making-for-an-estrogen-receptor-positive-advanced-breast-cancer-patient
#10
Bing Xu, Amy Krie, Pradip De, Casey Williams, Rachel Elsey, Jessica Klein, Brian Leyland-Jones
Breast cancer affects 12% of females in the United States and is the leading cause of cancer death in the female population. Personalized therapy is being used in clinical practice to treat breast cancer based on tumor molecular profiling, which can be obtained from tissue biopsy or plasma liquid biopsy as circulating tumor deoxyribonucleic acid (ctDNA). The available ctDNA tests provide a non-invasive way to monitor the cancer genome in a real-time manner. In this case report, a 38-year-old female with recurrent estrogen receptor (ER) positive breast cancer is treated with letrozole, everolimus, and palbociclib...
June 29, 2017: Curēus
https://www.readbyqxmd.com/read/28846108/runx3-plays-a-critical-role-in-restriction-point-and-defense-against-cellular-transformation
#11
X-Z Chi, J-W Lee, Y-S Lee, I Y Park, Y Ito, S-C Bae
The restriction (R)-point decision is fundamental to normal differentiation and the G1-S transition, and the decision-making machinery is perturbed in nearly all cancer cells. The mechanisms underlying the cellular context-dependent R-point decision remain poorly understood. We found that the R-point was dysregulated in Runx3(-/-)mouse embryonic fibroblasts (MEFs), which formed tumors in nude mice. Ectopic expression of Runx3 restored the R-point and abolished the tumorigenicity of Runx3(-/-)MEFs and K-Ras-activated Runx3(-/-)MEFs (Runx3(-/-);K-Ras(G12D/+))...
August 28, 2017: Oncogene
https://www.readbyqxmd.com/read/28844173/clinical-application-of-whole-genome-array-improves-the-diagnosis-of-pediatric-brain-tumors
#12
Lina Shao, Sue Miller, Carl Koschmann, Sandra Camelo-Piragua
Pediatric brain tumors are the leading cause of childhood cancer mortality. Recurring genetic abnormalities play an essential role in the diagnosis and prognosis of pediatric brain tumors. However, clinical workup has not routinely included whole genome assessment. Here, we present high resolution whole genome array results in 11 pediatric brain tumors. Array identified clinically relevant abnormalities in all samples. Copy number aberrations with targeted therapy implication, GOPC-ROS1 fusion, CDK4 amplification, and NF1 deletion, were detected in 3 cases...
August 1, 2017: International Journal of Surgical Pathology
https://www.readbyqxmd.com/read/28819400/rapid-breast-cancer-disease-progression-following-cyclin-dependent-kinase-4-and-6-inhibitor-discontinuation
#13
Sami I Bashour, Iman Doostan, Khandan Keyomarsi, Vicente Valero, Naoto T Ueno, Powel H Brown, Jennifer K Litton, Kimberly B Koenig, Meghan Karuturi, Sausan Abouharb, Debasish Tripathy, Stacy L Moulder-Thompson, Nuhad K Ibrahim
Background: CDK 4 and 6 inhibitors (CDK4/6i), which arrest unregulated cancer cell proliferation, show clinical efficacy in breast cancer. Unexpectedly, a patient treated on a CDK4/6i-based trial, as first-line therapy in metastatic breast cancer, developed rapid disease progression following discontinuation of study drug while receiving standard second-line therapy off trial. We thus sought to expand this observation within a population of patients treated similarly at The University of Texas MD Anderson Cancer Center...
2017: Journal of Cancer
https://www.readbyqxmd.com/read/28814434/combined-cdk4-6-and-mtor-inhibition-is-synergistic-against-glioblastoma-via-multiple-mechanisms
#14
Inan Olmez, Breanna Brenneman, Aizhen Xiao, Vlad Serbulea, Mouadh Benamar, Ying Zhang, Laryssa Manigat, Tarek Abbas, Jeongwu Lee, Ichiro Nakano, Jakub Godlewski, Agnieszka Bronisz, Roger Abounader, Norbert Leitinger, Benjamin Purow
PURPOSE: Glioblastoma (GBM) is a deadly brain tumor marked by dysregulated signaling and aberrant cell cycle control. Molecular analyses have identified that the CDK4/6-Rb-E2F axis is dysregulated in about 80% of GBMs. Single-agent CDK4/6 inhibitors have failed to provide durable responses in GBM, suggesting a need to combine them with other agents. We investigate the efficacy of the combination of CDK4/6 inhibition and mTOR inhibition against GBM. EXPERIMENTAL DESIGN: Preclinical in vitro and in vivo assays using primary GBM cell lines were performed...
August 16, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/28813415/cdk4-6-inhibition-triggers-anti-tumour-immunity
#15
Shom Goel, Molly J DeCristo, April C Watt, Haley BrinJones, Jaclyn Sceneay, Ben B Li, Naveed Khan, Jessalyn M Ubellacker, Shaozhen Xie, Otto Metzger-Filho, Jeremy Hoog, Matthew J Ellis, Cynthia X Ma, Susanne Ramm, Ian E Krop, Eric P Winer, Thomas M Roberts, Hye-Jung Kim, Sandra S McAllister, Jean J Zhao
Cyclin-dependent kinases 4 and 6 (CDK4/6) are fundamental drivers of the cell cycle and are required for the initiation and progression of various malignancies. Pharmacological inhibitors of CDK4/6 have shown significant activity against several solid tumours. Their primary mechanism of action is thought to be the inhibition of phosphorylation of the retinoblastoma tumour suppressor, inducing G1 cell cycle arrest in tumour cells. Here we use mouse models of breast carcinoma and other solid tumours to show that selective CDK4/6 inhibitors not only induce tumour cell cycle arrest, but also promote anti-tumour immunity...
August 24, 2017: Nature
https://www.readbyqxmd.com/read/28801307/loss-of-mutl-disrupts-chk2-dependent-cell-cycle-control-through-cdk4-6-to-promote-intrinsic-endocrine-therapy-resistance-in-primary-breast-cancer
#16
Svasti Haricharan, Nindo Punturi, Purba Singh, Kimberly R Holloway, Meenakshi Anurag, Jacob Schmelz, Cheryl Schmidt, Jonathan T Lei, Vera Suman, Kelly Hunt, John A Olson, Jeremy Hoog, Shunqiang Li, Shixia Huang, Dean P Edwards, Shyam M Kavuri, Matthew N Bainbridge, Cynthia X Ma, Matthew J Ellis
Significant endocrine therapy-resistant tumor proliferation is present in ≥20% of estrogen receptor positive (ER+) primary breast cancers and is associated with disease recurrence and death. Here, we uncover a link between intrinsic endocrine therapy resistance and dysregulation of the MutL mismatch repair complex (MLH1/3, PMS1/2), and demonstrate a direct role for MutL complex loss in resistance to all classes of endocrine therapy. We find that MutL deficiency in ER+ breast cancer abrogates Chk2-mediated inhibition of CDK4, a prerequisite for endocrine therapy responsiveness...
August 11, 2017: Cancer Discovery
https://www.readbyqxmd.com/read/28800675/discovery-and-pharmacological-characterisation-of-a-novel-series-of-highly-selective-inhibitors-of-cyclin-dependent-kinases-4-and-6-as-anticancer-agents
#17
Solomon Tadesse, Laychiluh Bantie, Khamis Tomusange, Mingfeng Yu, Saiful Islam, Nataliya Bykovska, Benjamin Noll, Ge Zhu, Peng Li, Frankie Lam, Malika Kumarasiri, Robert Milne, Shudong Wang
BACKGROUND AND PURPOSE: Cyclin D dependent kinases 4 and 6 (CDK4/6) are crucial regulators of the G1 to S phase transition of the cell cycle, and are actively pursued as therapeutic targets in cancer targets. We sought to discover a novel series of orally bioavailable, and highly selective small molecule inhibitors of CDK4/6. EXPERIMENTAL APPROACH: The discovery of pharmacological inhibitors and optimisation for potency, selectivity and drug properties were achieved by iterative chemical synthesis, biochemical screening against a panel of kinases, cell-based assays measuring cellular viability, cell cycle distribution, induction of apoptosis, and the level of retinoblastoma tumour suppressor protein (Rb) phosphorylation and E2 factor (E2F) regulated gene expression, and in vitro biopharmaceutical and in vivo pharmacokinetic profiling...
August 11, 2017: British Journal of Pharmacology
https://www.readbyqxmd.com/read/28795589/a-novel-series-of-n-pyridin-2-yl-4-thiazol-5-yl-pyrimidin-2-amines-as-highly-potent-cdk4-6-inhibitors
#18
Solomon Tadesse, Ge Zhu, Laychiluh B Mekonnen, Jimma L Lenjisa, Mingfeng Yu, Michael P Brown, Shudong Wang
AIM: Inhibitors of CDK4/6 have emerged as a powerful class of therapeutics for treatment of several malignancies. We herein describe the identification of a new series of molecules that demonstrated excellent selectivity for CDK4/6 over CDKs1, 7 and 9. RESULTS: Medicinal chemistry optimization led to the discovery of 58 and 69 that inhibited CDK4 and CDK4/6, respectively, with high potency and selectivity, and 58 and 69 exhibited potent antiproliferative activities in a panel of human cancer cell lines including leukemia, and cancers of the breast, colon, ovary, pancreas and prostate...
August 10, 2017: Future Medicinal Chemistry
https://www.readbyqxmd.com/read/28794284/genomic-profiling-of-er-breast-cancers-after-short-term-estrogen-suppression-reveals-alterations-associated-with-endocrine-resistance
#19
Jennifer M Giltnane, Katherine E Hutchinson, Thomas P Stricker, Luigi Formisano, Christian D Young, Monica V Estrada, Mellissa J Nixon, Liping Du, Violeta Sanchez, Paula Gonzalez Ericsson, Maria G Kuba, Melinda E Sanders, Xinmeng J Mu, Eliezer M Van Allen, Nikhil Wagle, Ingrid A Mayer, Vandana Abramson, Henry Gόmez, Monica Rizzo, Weiyi Toy, Sarat Chandarlapaty, Erica L Mayer, Jason Christiansen, Danielle Murphy, Kerry Fitzgerald, Kai Wang, Jeffrey S Ross, Vincent A Miller, Phillip J Stephens, Roman Yelensky, Levi Garraway, Yu Shyr, Ingrid Meszoely, Justin M Balko, Carlos L Arteaga
Inhibition of proliferation in estrogen receptor-positive (ER(+)) breast cancers after short-term antiestrogen therapy correlates with long-term patient outcome. We profiled 155 ER(+)/human epidermal growth factor receptor 2-negative (HER2(-)) early breast cancers from 143 patients treated with the aromatase inhibitor letrozole for 10 to 21 days before surgery. Twenty-one percent of tumors remained highly proliferative, suggesting that these tumors harbor alterations associated with intrinsic endocrine therapy resistance...
August 9, 2017: Science Translational Medicine
https://www.readbyqxmd.com/read/28760782/cdk4-6-inhibition-on-glucose-and-pancreatic-beta-cell-homeostasis-in-young-and-aged-rats
#20
Aida I Sacaan, Stephane Thibault, Miyoun Hong, Nagesha G Kondegowda, Timothy C Nichols, Rosemary Li, Carolina Rosselot, Winston Evering, Rafael Fenutria, Allison Vitsky, Thomas Brown, Martin B Finkelstein, Adolfo Garcia-Ocaña, Nasir K Khan, Andrew F Stewart, Rupangi C Vasavada
Genetic deletion of cyclin-dependent kinase 4 (CDK4) is associated with pancreatic beta cell loss and glucose dysregulation in rodents. Palbociclib, one of the first selective CDK4/6 inhibitors approved for the treatment of advanced breast cancer, is currently being investigated as an adjuvant treatment in patients with early-stage breast cancer and in a variety of cancers covering a wide-range of patient populations. Hence, longer chronic toxicity studies were necessary to further examine its safety profile...
July 31, 2017: Molecular Cancer Research: MCR
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