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https://www.readbyqxmd.com/read/28404914/the-preclinical-assessment-of-xl388-a-mtor-kinase-inhibitor-as-a-promising-anti-renal-cell-carcinoma-agent
#1
Zuquan Xiong, Yiwen Zang, Shan Zhong, Lujia Zou, Yishuo Wu, Shenghua Liu, Zujun Fang, Zhoujun Shen, Qiang Ding, Shanwen Chen
XL388 is a mammalian target of rapamycin (mTOR) kinase inhibitor. We demonstrated that XL388 inhibited survival and proliferation of renal cell carcinoma (RCC) cell lines (786-0 and A549) and primary human RCC cells. XL388 activated caspase-dependent apoptosis in the RCC cells. XL388 blocked mTOR complex 1 (mTORC1) and mTORC2 activation, and depleted hypoxia-inducible factor 1α (HIF1α) and HIF-2α expression in RCC cells. Yet, XL388 was ineffective in RCC cells with mTOR shRNA knockdown or kinase-dead mutation...
February 22, 2017: Oncotarget
https://www.readbyqxmd.com/read/28248226/activity-based-proteomics-reveals-heterogeneous-kinome-and-atp-binding-proteome-responses-to-mek-inhibition-in-kras-mutant-lung-cancer
#2
Jae-Young Kim, Paul A Stewart, Adam L Borne, Bin Fang, Eric A Welsh, Yian Ann Chen, Steven A Eschrich, John M Koomen, Eric B Haura
One way cancer cells can escape from targeted agents is through their ability to evade drug effects by rapidly rewiring signaling networks. Many protein classes, such as kinases and metabolic enzymes, are regulated by ATP binding and hydrolysis. We hypothesized that a system-level profiling of drug-induced alterations in ATP-binding proteomes could offer novel insights into adaptive responses. Here, we mapped global ATP-binding proteomes perturbed by two clinical MEK inhibitors, AZD6244 and MEK162, in KRAS mutant lung cancer cells as a model system harnessing a desthiobiotin-ATP probe coupled with LC-MS/MS...
April 27, 2016: Proteomes
https://www.readbyqxmd.com/read/28154798/activity-based-proteomics-reveals-heterogeneous-kinome-and-atp-binding-proteome-responses-to-mek-inhibition-in-kras-mutant-lung-cancer
#3
Jae-Young Kim, Paul A Stewart, Adam L Borne, Bin Fang, Eric A Welsh, Yian Ann Chen, Steven A Eschrich, John M Koomen, Eric B Haura
One way cancer cells can escape from targeted agents is through their ability to evade drug effects by rapidly rewiring signaling networks. Many protein classes, such as kinases and metabolic enzymes, are regulated by ATP binding and hydrolysis. We hypothesized that a system-level profiling of drug-induced alterations in ATP-binding proteomes could offer novel insights into adaptive responses. Here, we mapped global ATP-binding proteomes perturbed by two clinical MEK inhibitors, AZD6244 and MEK162, in KRAS mutant lung cancer cells as a model system harnessing a desthiobiotin-ATP probe coupled with LC-MS/MS...
June 2016: Proteomes
https://www.readbyqxmd.com/read/28152546/a-phase-1-dose-escalation-and-expansion-study-of-binimetinib-mek162-a-potent-and-selective-oral-mek1-2-inhibitor
#4
Johanna C Bendell, Milind Javle, Tanios S Bekaii-Saab, Richard S Finn, Zev A Wainberg, Daniel A Laheru, Colin D Weekes, Benjamin R Tan, Gazala N Khan, Mark M Zalupski, Jeffrey R Infante, Suzanne Jones, Kyriakos P Papadopoulos, Anthony W Tolcher, Renae E Chavira, Janna L Christy-Bittel, Emma Barrett, Amita Patnaik
BACKGROUND: Binimetinib (MEK162; ARRY-438162) is a potent and selective oral MEK 1/2 inhibitor. This phase 1 study determined the maximum tolerated dose (MTD), safety, pharmacokinetic and pharmacodynamic profiles, and preliminary anti-tumour activity of binimetinib in patients with advanced solid tumours, with expansion cohorts of patients with biliary cancer or KRAS- or BRAF-mutant colorectal cancer. METHODS: Binimetinib was administered twice daily. Expansion cohorts were enroled after MTD determination following a 3+3 dose-escalation design...
February 28, 2017: British Journal of Cancer
https://www.readbyqxmd.com/read/27811010/dual-inhibition-of-mek-and-pi3k-akt-rescues-cancer-cachexia-through-both-tumor-extrinsic-and-intrinsic-activities
#5
Erin E Talbert, Jennifer Yang, Thomas A Mace, Matthew R Farren, Alton B Farris, Gregory S Young, Omar Elnaggar, Zheng Che, Cynthia D Timmers, Priyani Rajasekera, Jennifer M Maskarinec, Mark Bloomston, Tanios Bekaii-Saab, Denis C Guttridge, Gregory B Lesinski
Involuntary weight loss, a part of the cachexia syndrome, is a debilitating comorbidity of cancer and currently has no treatment options. Results from a recent clinical trial at our institution showed that biliary tract cancer patients treated with a MEK inhibitor exhibited poor tumor responses but surprisingly gained weight and increased their skeletal muscle mass. This implied that MEK inhibition might be anticachectic. To test this potential effect of MEK inhibition, we utilized the established Colon-26 model of cancer cachexia and the MEK1/2 inhibitor MEK162...
February 2017: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/27793696/baseline-mapk-signaling-activity-confers-intrinsic-radioresistance-to-kras-mutant-colorectal-carcinoma-cells-by-rapid-upregulation-of-heterogeneous-nuclear-ribonucleoprotein-k-hnrnp-k
#6
Stefan Eder, Annette Arndt, Andreas Lamkowski, Wassiliki Daskalaki, Alexis Rump, Markus Priller, Felicitas Genze, Eva Wardelmann, Matthias Port, Konrad Steinestel
Heterogeneous nuclear ribonucleoprotein K (hnRNP K) is overexpressed in malignant tumors and involved in DNA damage response upon ionizing radiation (IR). Here, we investigate its role in radioresistance of colorectal carcinoma (CRC) and evaluate a pharmacological approach to enhance CRC radiosensitivity via downregulation of hnRNP K. We show that hnRNP K is overexpressed in CRC tissue specimens and upregulated in response to IR in vitro, which occurs faster in KRAS-mutant CRC cells. HnRNP K knockdown impairs cell survival, cell cycle progression and KRAS-dependent radioresistance and increases apoptosis...
January 28, 2017: Cancer Letters
https://www.readbyqxmd.com/read/27751856/ampk-activation-by-gsk621-inhibits-human-melanoma-cells-in-vitro-and-in-vivo
#7
Lezi Chen, Quan Chen, Guosan Deng, Wenbin Xie, Jihong Lian, Mian Wang, Huilan Zhu
Recent studies suggest that forced activation of AMP-activated protein kinase (AMPK) could inhibit melanoma cell proliferation. In this report, we evaluated the anti-melanoma cell activity by a novel small-molecular AMPK activator, GSK621. Treatment of GSK621 decreased survival and proliferation of human melanoma cells (A375, WM-115 and SK-Mel-2 lines), which was accompanied by activation of caspase-3/-9 and apoptosis. Reversely, caspase inhibitors attenuated GSK621-induced cytotoxicity against melanoma cells...
October 14, 2016: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/27588400/mek-inhibition-is-a-promising-therapeutic-strategy-for-mll-rearranged-infant-acute-lymphoblastic-leukemia-patients-carrying-ras-mutations
#8
Mark Kerstjens, Emma M C Driessen, Merel Willekes, Sandra S Pinhanços, Pauline Schneider, Rob Pieters, Ronald W Stam
Acute lymphoblastic leukemia (ALL) in infants is an aggressive malignancy with a poor clinical outcome, and is characterized by translocations of the Mixed Lineage Leukemia (MLL) gene. Previously, we identified RAS mutations in 14-24% of infant ALL patients, and showed that the presence of a RAS mutation decreased the survival chances even further. We hypothesized that targeting the RAS signaling pathway could be a therapeutic strategy for RAS-mutant infant ALL patients. Here we show that the MEK inhibitors Trametinib, Selumetinib and MEK162 severely impair primary RAS-mutant MLL-rearranged infant ALL cells in vitro...
February 28, 2017: Oncotarget
https://www.readbyqxmd.com/read/27576686/expression-of-death-receptor-4-is-positively-regulated-by-mek-erk-ap-1-signaling-and-suppressed-upon-mek-inhibition
#9
Weilong Yao, You-Take Oh, Jiusheng Deng, Ping Yue, Liang Deng, Henry Huang, Wei Zhou, Shi-Yong Sun
Death receptor 4 (DR4) is a cell surface receptor for tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and triggers apoptosis upon ligation with TRAIL or aggregation. MEK/ERK signaling is a well known and the best-studied effector pathway downstream of Ras and Raf. This study focuses on determining the impact of pharmacological MEK inhibition on DR4 expression and elucidating the underlying mechanism. We found that several MEK inhibitors including MEK162, AZD6244, and PD0325901 effectively decreased DR4 protein levels including cell surface DR4 in different cancer cell lines...
October 7, 2016: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/27462917/targeting-of-the-mapk-and-akt-pathways-in-conjunctival-melanoma-shows-potential-synergy
#10
Jinfeng Cao, Renier C Heijkants, Aart G Jochemsen, Mehmet Dogrusöz, Mark J de Lange, Pieter A van der Velden, Sjoerd H van der Burg, Martine J Jager, Robert M Verdijk
PURPOSE: Conjunctival melanoma (CM) is a rare but lethal form of cancer. Similar to cutaneous melanoma, CM frequently carries activating mutations in BRAF and NRAS. We studied whether CM as well as conjunctival benign and premalignant melanocytic lesions express targets in the mitogen-activated protein kinase (MAPK) and AKT pathways, and whether specific inhibitors can suppress CM growth in vitro. METHODS: 131 conjunctival lesions obtained from 129 patients were collected...
July 22, 2016: Oncotarget
https://www.readbyqxmd.com/read/27167191/efficacy-of-the-combination-of-mek-and-cdk4-6-inhibitors-in-vitro-and-in-vivo-in-kras-mutant-colorectal-cancer-models
#11
Michael S Lee, Timothy L Helms, Ningping Feng, Jason Gay, Qing Edward Chang, Feng Tian, Ji Y Wu, Carlo Toniatti, Timothy P Heffernan, Garth Powis, Lawrence N Kwong, Scott Kopetz
PURPOSE: Though the efficacy of MEK inhibitors is being investigated in KRAS-mutant colorectal cancers (CRC), early clinical trials of MEK inhibitor monotherapy did not reveal significant antitumor activity. Resistance to MEK inhibitor monotherapy developed through a variety of mechanisms converging in ERK reactivation. Since ERK increases cyclin D expression and increases entry into the cell cycle, we hypothesized that the combination of MEK inhibitors and CDK4/6 inhibitors would have synergistic antitumor activity and cause tumor regression in vivo...
June 28, 2016: Oncotarget
https://www.readbyqxmd.com/read/27071922/a-phase-i-study-of-binimetinib-mek162-in-japanese-patients-with-advanced-solid-tumors
#12
K Watanabe, S Otsu, Y Hirashima, R Morinaga, K Nishikawa, Y Hisamatsu, T Shimokata, M Inada-Inoue, T Shibata, H Takeuchi, T Watanabe, K Tokushige, H Maacke, K Shiaro, Y Ando
PURPOSE: Binimetinib is a potent, selective MEK1/2 inhibitor with demonstrated efficacy against BRAF- and RAS-mutant tumors. Retinal adverse events associated with MEK inhibitors have been reported in some cases. The aim of this study was to assess single-agent binimetinib, with detailed ophthalmologic monitoring, in Japanese patients with advanced solid tumors. METHODS: This was an open-label phase I dose-escalation and dose-expansion study (NCT01469130). Adult patients with histologically confirmed, evaluable, advanced solid tumors were enrolled and treated with binimetinib 30 or 45 mg twice daily (BID)...
2016: Cancer Chemotherapy and Pharmacology
https://www.readbyqxmd.com/read/26821351/targeting-the-mtor-complex-by-everolimus-in-nras-mutant-neuroblastoma
#13
Michael K Kiessling, Alessandra Curioni-Fontecedro, Panagiotis Samaras, Silvia Lang, Michael Scharl, Adriano Aguzzi, Derek A Oldrige, John M Maris, Gerhard Rogler
High-risk neuroblastoma remains lethal in about 50% of patients despite multimodal treatment. Recent attempts to identify molecular targets for specific therapies have shown that Neuroblastoma RAS (NRAS) is significantly mutated in a small number of patients. However, few inhibitors for the potential treatment for NRAS mutant neuroblastoma have been investigated so far. In this in-vitro study, we show that MEK inhibitors AZD6244, MEK162 and PD0325901 block cell growth in NRAS mutant neuroblastoma cell lines but not in NRAS wild-type cell lines...
2016: PloS One
https://www.readbyqxmd.com/read/26683364/whole-exome-tumor-sequencing-study-in-biliary-cancer-patients-with-a-response-to-mek-inhibitors
#14
Daniel H Ahn, Hatice Gulcin Ozer, Baris Hancioglu, Gregory B Lesinski, Cynthia Timmers, Tanios Bekaii-Saab
We previously conducted a phase-II study with selumetinib (AZD6244), a small molecule inhibitor of MEK1/2, in advanced biliary tract cancers (BTC), where the primary endpoint was response rate. Several patients experienced objective response. These findings were confirmed with MEK162 in a similar patient population. To assess for tumor-specific genetic variants that mediate sensitivity to MEK inhibition in BTC, we performed whole-exome sequencing in patients with an objective response to selumetinib. Normal and tumor DNA from FFPE tissue from two patients who experienced an objective response underwent whole-exome sequencing...
February 2, 2016: Oncotarget
https://www.readbyqxmd.com/read/26544513/mutant-hras-as-novel-target-for-mek-and-mtor-inhibitors
#15
Michael K Kiessling, Alessandra Curioni-Fontecedro, Panagiotis Samaras, Kirstin Atrott, Jesus Cosin-Roger, Silvia Lang, Michael Scharl, Gerhard Rogler
HRAS is a frequently mutated oncogene in cancer. However, mutant HRAS as drug target has not been investigated so far. Here, we show that mutant HRAS hyperactivates the RAS and the mTOR pathway in various cancer cell lines including lung, bladder and esophageal cancer. HRAS mutation sensitized toward growth inhibition by the MEK inhibitors AZD6244, MEK162 and PD0325901. Further, we found that MEK inhibitors induce apoptosis in mutant HRAS cell lines but not in cell lines lacking RAS mutations. In addition, knockdown of HRAS by siRNA blocked cell growth in mutant HRAS cell lines...
December 8, 2015: Oncotarget
https://www.readbyqxmd.com/read/26354928/nevospheres-from-neurocutaneous-melanocytosis-cells-show-reduced-viability-when-treated-with-specific-inhibitors-of-nras-signaling-pathway
#16
Dipanjan Basu, Cláudia M Salgado, Bruce S Bauer, Donald Johnson, Veronica Rundell, Marina Nikiforova, Yasmin Khakoo, Lorelei J Gunwaldt, Ashok Panigrahy, Miguel Reyes-Múgica
BACKGROUND: Neurocutaneous melanocytosis (NCM) is characterized by clonal nevomelanocytic proliferations in the CNS and skin. Given the scarcity of effective therapeutic targets, testing new drugs requires a reliable and reproducible in vitro cellular model of the disease. METHODS: We generated nevomelanocytic spheroids in vitro from lesions of the spinal cord, brain, and skin from 4 NCM patients. Nevomelanocytic cells were grown as monolayers or spheroids and their growth characteristics were evaluated...
April 2016: Neuro-oncology
https://www.readbyqxmd.com/read/26053277/drug-induced-raf-dimerization-is-independent-of-ras-mutation-status-and-does-not-lead-to-universal-mek-dependence-for-cell-survival-in-head-and-neck-cancers
#17
Tuhina Mazumdar, Banibrata Sen, Yifan Wang, Shaohua Peng, Courtney Nicholas, Bonnie S Glisson, Jeffrey N Myers, Faye M Johnson
Treatments for recurrent or metastatic head and neck squamous cell carcinoma (HNSCC) have limited efficacy. One potential therapeutic target for HNSCC is the RAS/RAF/MEK/ERK cascade, which is one of the major signaling pathways for HNSCC cell survival. In HNSCC, RAS can be activated either by HRAS mutation or by upstream signaling. The ABL inhibitor nilotinib acts as a weak RAF inhibitor that induces RAF dimerization and subsequent activation of MEK/ERK in other cancer cell lines with activated RAS, leading to an unexpected dependence on MEK/ERK for cell survival...
September 2015: Anti-cancer Drugs
https://www.readbyqxmd.com/read/25937299/enhancing-therapeutic-efficacy-of-the-mek-inhibitor-mek162-by-blocking-autophagy-or-inhibiting-pi3k-akt-signaling-in-human-lung-cancer-cells
#18
Weilong Yao, Ping Yue, Guojing Zhang, Taofeek K Owonikoko, Fadlo R Khuri, Shi-Yong Sun
Human non-small cell lung cancer (NSCLC) displays activated MEK/ERK signaling due to a high frequency of K-Ras mutation and is thus a potential candidate for MEK-targeted therapy. The current study focuses on demonstrating the activity of MEK162 (binimetinib), a MEK inhibitor under clinical testing, against NSCLC and exploring possible mechanism-driven strategies to enhance its therapeutic efficacy. MEK162 inhibits the growth of human NSCLC cell lines with varied potencies through induction of G1 cell cycle arrest and apoptosis...
August 1, 2015: Cancer Letters
https://www.readbyqxmd.com/read/25788221/clinical-observation-of-panniculitis-in-two-patients-with-braf-mutated-metastatic-melanoma-treated-with-a-combination-of-a-braf-inhibitor-and-a-mek-inhibitor
#19
Nadja A Galliker, Carla Murer, Jivko Kamarashev, Reinhard Dummer, Simone M Goldinger
BACKGROUND: Treatment with selective BRAF or MEK inhibitors is frequently associated with cutaneous toxicities, including squamous cell carcinoma (SCC), papillomas and rash. These cutaneous adverse effects are typically observed at a lower incidence during combined BRAF and MEK inhibitor therapy. PATIENTS AND METHODS: Two male patients with stage IV metastatic BRAF-mutated melanoma were treated with a combination of a selective BRAF inhibitor and a selective MEK inhibitor (dabrafenib and trametinib, or encorafenib (LGX818) and binimetinib (MEK162)) within two different clinical trials...
April 2015: European Journal of Dermatology: EJD
https://www.readbyqxmd.com/read/25624003/increasing-progranulin-levels-and-blockade-of-the-erk1-2-pathway-upstream-and-downstream-strategies-for-the-treatment-of-progranulin-deficient-frontotemporal-dementia
#20
Carolina Alquezar, Noemí Esteras, Ana de la Encarnación, Fermín Moreno, Adolfo López de Munain, Ángeles Martín-Requero
Frontotemporal lobar degeneration (FTLD) is a neurodegenerative disorder marked by mild-life onset and progressive changes in behavior, social cognition, and language. Loss-of-function progranulin gene (GRN) mutations are the major cause of FTLD with TDP-43 protein inclusions (FTLD-TDP). Disease-modifying treatments for FTLD-TDP are not available yet. Mounting evidence indicates that cell cycle dysfunction may play a pathogenic role in neurodegenerative disorders including FTLD. Since cell cycle re-entry of posmitotic neurons seems to precede neuronal death, it was hypothesized that strategies aimed at preventing cell cycle progression would have neuroprotective effects...
March 2015: European Neuropsychopharmacology: the Journal of the European College of Neuropsychopharmacology
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