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https://www.readbyqxmd.com/read/28222227/recurrent-tattoo-reactions-in-a-patient-treated-with-braf-and-mek-inhibitors
#1
Raphael Reinhard, Christoffer Gebhardt, Astrid Schmieder, Viktor Umansky, Jochen Utikal
Commonly tattoo reactions are acute occurrences in correspondence to tattoo ink. They usually present during the first 2 to 3 weeks, after the tattoo was done. Tattoo reactions can be classified as acute inflammatory reactions, allergic hypersensitivities, granulomatous and pseudolymphomatous types of reactions.(1) This article is protected by copyright. All rights reserved.
February 21, 2017: Journal of the European Academy of Dermatology and Venereology: JEADV
https://www.readbyqxmd.com/read/28220839/pten-status-is-a-crucial-determinant-of-the-functional-outcome-of-combined-mek-and-mtor-inhibition-in-cancer
#2
Michele Milella, Italia Falcone, Fabiana Conciatori, Silvia Matteoni, Andrea Sacconi, Teresa De Luca, Chiara Bazzichetto, Vincenzo Corbo, Michele Simbolo, Isabella Sperduti, Antonina Benfante, Anais Del Curatolo, Ursula Cesta Incani, Federico Malusa, Adriana Eramo, Giovanni Sette, Aldo Scarpa, Marina Konopleva, Michael Andreeff, James Andrew McCubrey, Giovanni Blandino, Matilde Todaro, Giorgio Stassi, Ruggero De Maria, Francesco Cognetti, Donatella Del Bufalo, Ludovica Ciuffreda
Combined MAPK/PI3K pathway inhibition represents an attractive, albeit toxic, therapeutic strategy in oncology. Since PTEN lies at the intersection of these two pathways, we investigated whether PTEN status determines the functional response to combined pathway inhibition. PTEN (gene, mRNA, and protein) status was extensively characterized in a panel of cancer cell lines and combined MEK/mTOR inhibition displayed highly synergistic pharmacologic interactions almost exclusively in PTEN-loss models. Genetic manipulation of PTEN status confirmed a mechanistic role for PTEN in determining the functional outcome of combined pathway blockade...
February 21, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28220783/an-integrative-approach-unveils-fosl1-as-an-oncogene-vulnerability-in-kras-driven-lung-and-pancreatic-cancer
#3
Adrian Vallejo, Naiara Perurena, Elisabet Guruceaga, Pawel K Mazur, Susana Martinez-Canarias, Carolina Zandueta, Karmele Valencia, Andrea Arricibita, Dana Gwinn, Leanne C Sayles, Chen-Hua Chuang, Laura Guembe, Peter Bailey, David K Chang, Andrew Biankin, Mariano Ponz-Sarvise, Jesper B Andersen, Purvesh Khatri, Aline Bozec, E Alejandro Sweet-Cordero, Julien Sage, Fernando Lecanda, Silve Vicent
KRAS mutated tumours represent a large fraction of human cancers, but the vast majority remains refractory to current clinical therapies. Thus, a deeper understanding of the molecular mechanisms triggered by KRAS oncogene may yield alternative therapeutic strategies. Here we report the identification of a common transcriptional signature across mutant KRAS cancers of distinct tissue origin that includes the transcription factor FOSL1. High FOSL1 expression identifies mutant KRAS lung and pancreatic cancer patients with the worst survival outcome...
February 21, 2017: Nature Communications
https://www.readbyqxmd.com/read/28220250/differing-roles-for-sur-2-med23-in-c-elegans-and-c-briggsae-vulval-development
#4
Karley K Mahalak, Abdulrahman M Jama, Steven J Billups, Adriana T Dawes, Helen M Chamberlin
Normal vulval development in the nematode Caenorhabditis briggsae is identical to that in the related Caenorhabditis elegans. However, several experiments suggest that there are differences between the two species with respect to the contribution of EGF/Ras signaling. To investigate these differences genetically, we have characterized a C. briggsae mutant strain that phenocopies the effect observed when C. briggsae animals are treated with U0126, an inhibitor of the EGF pathway component MEK. We identify that the gene affected in the mutant strain is Cbr-sur-2, which encodes a MED23 mediator complex protein that acts downstream of EGF signaling in C...
February 20, 2017: Development Genes and Evolution
https://www.readbyqxmd.com/read/28220061/a-model-of-induction-of-cerebellar-long-term-depression-including-rkip-inactivation-of-raf-and-mek
#5
Iain Hepburn, Anant Jain, Himanshu Gangal, Yukio Yamamoto, Keiko Tanaka-Yamamoto, Erik De Schutter
We report an updated stochastic model of cerebellar Long Term Depression (LTD) with improved realism. Firstly, we verify experimentally that dissociation of Raf kinase inhibitor protein (RKIP) from Mitogen-activated protein kinase kinase (MEK) is required for cerebellar LTD and add this interaction to an earlier published model, along with the known requirement of dissociation of RKIP from Raf kinase. We update Ca(2+) dynamics as a constant-rate influx, which captures experimental input profiles accurately...
2017: Frontiers in Molecular Neuroscience
https://www.readbyqxmd.com/read/28218307/effects-of-u0126-and-mk2206-on-cell-growth-and-re-growth-of-endometriotic-stromal-cells-grown-on-substrates-of-varying-stiffness
#6
Sachiko Matsuzaki, Jean-Luc Pouly, Michel Canis
Endometriosis is a common gynecological disorder responsible for infertility and pelvic pain. A complete cure for patients with endometriosis awaits new targets and strategies. Here we show that U0126 (a MEK inhibitor) and MK2206 (an AKT inhibitor) synergistically inhibit cell growth of deep endometriotic stromal cells (DES) grown on polyacrylamide gel substrates (PGS) of varying stiffness (2 or 30 kilopascal [kPa]) or plastic in vitro. No significant differences in cell proliferation were observed among DES, endometrial stromal cells of patients with endometriosis (EES) from the proliferative phase (P), EES-S (secretory phase) and EES-M (menstrual phase) compared to cells grown on a substrate of the same stiffness at both higher (U0126 [30 μM] and MK2206 [9 μM]) and lower (U0126 [15 μM] and MK2206 [4...
February 20, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28216156/epac-mediates-camp-induced-proliferation-of-rat-anterior-pituitary-gh3-cells-via-the-activation-of-extracellular-signal-regulated-kinase
#7
Wei Sun, Wei Jiao, Yimin Huang, Ran Li, Zhuo Zhang, Junwen Wang, Ting Lei
Cyclic adenosine 3'-5'-monophosphate (cAMP) plays a crucial role in regulating pituitary cell proliferation and hormone synthesis. Recent evidence suggests that exchange proteins directly activated by cAMP (Epacs) may mediate the effects of cAMP. Here we used rat anterior pituitary GH3 cells as the experiment model to demonstrate that forskolin increased the proliferation of GH3 cells and the phosphorylation of ERK1/2, and these effects were inhibited by PKA or Epac inhibitors. Epac activator 8-pCPT-2'-O-Me-cAMP increased GH3 cell proliferation and this was blocked by ESI-09, an Epac inhibitor...
February 16, 2017: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/28215740/inhibition-of-htert-expression-by-map-kinase-inhibitor-induces-cell-death-in-renal-cell-carcinoma
#8
Deeksha Pal, Ujjawal Sharma, Shrawan Kumar Singh, Nandita Kakkar, Rajendra Prasad
BACKGROUND: Human telomerase reverse transcriptase (hTERT) is one of the components of telomerase enzyme and its activity is associated with cell proliferation and differentiation. Extracellular signal regulated kinase (ERK)-mitogen activated protein kinase signaling pathway play an important role in hTERT expression. The present study was conducted to ascertain hTERT messenger RNA (mRNA) expression in renal cell carcinoma (RCC) and its association with clinicopathological characteristics...
February 16, 2017: Urologic Oncology
https://www.readbyqxmd.com/read/28215705/kras-allelic-imbalance-enhances-fitness-and-modulates-map-kinase-dependence-in-cancer
#9
Michael R Burgess, Eugene Hwang, Rana Mroue, Craig M Bielski, Anica M Wandler, Benjamin J Huang, Ari J Firestone, Amy Young, Jennifer A Lacap, Lisa Crocker, Saurabh Asthana, Elizabeth M Davis, Jin Xu, Keiko Akagi, Michelle M Le Beau, Qing Li, Benjamin Haley, David Stokoe, Deepak Sampath, Barry S Taylor, Marie Evangelista, Kevin Shannon
Investigating therapeutic "outliers" that show exceptional responses to anti-cancer treatment can uncover biomarkers of drug sensitivity. We performed preclinical trials investigating primary murine acute myeloid leukemias (AMLs) generated by retroviral insertional mutagenesis in Kras(G12D) "knockin" mice with the MEK inhibitor PD0325901 (PD901). One outlier AML responded and exhibited intrinsic drug resistance at relapse. Loss of wild-type (WT) Kras enhanced the fitness of the dominant clone and rendered it sensitive to MEK inhibition...
February 16, 2017: Cell
https://www.readbyqxmd.com/read/28214826/emodin-increases-expression-of-insulin-like-growth-factor-binding-protein-1-through-activation-of-mek-erk-ampk%C3%AE-and-interaction-of-ppar%C3%AE-and-sp1-in-lung-cancer
#10
Qing Tang, JingJing Wu, Fang Zheng, Swei Sunny Hann, YuQing Chen
BACKGROUND: Emodin has anti-neoplastic activities on multiple tumors. However, the molecular mechanisms underlying this effect still remain to be fully understood. METHODS: Cell viability and cell cycle distribution were measured using 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide (MTT) assays and flow cytometry, respectively. Cell invasion and migration were examined by transwell invasion and wound healing assays. Western blot analysis was performed to examine the phosphorylation and protein expression of AMP-activated protein kinase alpha (AMPKα), extracellular signaling-regulated kinase 1/2 (ERK1/2), peroxisome proliferators-activated receptor gamma (PPARγ), insulin-like growth factor (IGF) binding protein 1 (IGFBP1) and the transcription factor Sp1...
January 26, 2017: Cellular Physiology and Biochemistry
https://www.readbyqxmd.com/read/28212889/inhibition-of-proliferation-and-invasion-in-2d-and-3d-models-by-2-methoxyestradiol-in-human-melanoma-cells
#11
R R Massaro, F Faião-Flores, V W Rebecca, S Sandri, D K Alves-Fernandes, P C Pennacchi, K S M Smalley, S S Maria-Engler
Despite the recent advances in the clinical management of melanoma, there remains a need for new pharmacological approaches to treat this cancer. 2-methoxyestradiol (2ME) is a metabolite of estrogen that has shown anti-tumor effects in many cancer types. In this study we show that 2ME treatment leads to growth inhibition in melanoma cells, an effect associated with entry into senescence, decreased pRb and CyclinB1 expression, increased p21/Cip1 expression and G2/M cell cycle arrest. 2ME treatment also inhibits melanoma cell growth in colony formation assays, including cell lines with acquired resistance to BRAF and BRAF+MEK inhibitors...
February 14, 2017: Pharmacological Research: the Official Journal of the Italian Pharmacological Society
https://www.readbyqxmd.com/read/28212293/targeting-angiogenesis-in-biliary-tract-cancers-an-open-option
#12
REVIEW
Valeria Simone, Oronzo Brunetti, Luigi Lupo, Mario Testini, Eugenio Maiorano, Michele Simone, Vito Longo, Christian Rolfo, Marc Peeters, Aldo Scarpa, Amalia Azzariti, Antonio Russo, Domenico Ribatti, Nicola Silvestris
Biliary tract cancers (BTCs) are characterized by a bad prognosis and the armamentarium of drugs for their treatment is very poor. Although the inflammatory status of biliary tract represents the first step in the cancerogenesis, the microenvironment also plays a key role in the pathogenesis of BTCs, promoting tumor angiogenesis, invasion and metastasis. Several molecules, such as vascular endothelial growth factor (VEGF) and fibroblast growth factor (FGF), are involved in the angiogenesis process and their expression on tumor samples has been explored as prognostic marker in both cholangiocarcinoma and gallbladder cancer...
February 15, 2017: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/28210225/increased-apoptosis-in-the-paraventricular-nucleus-mediated-by-at1r-ras-erk1-2-signaling-results-in-sympathetic-hyperactivity-and-renovascular-hypertension-in-rats-after-kidney-injury
#13
Hongguo Zhu, Lishan Tan, Yumin Li, Jiawen Li, Minzi Qiu, Lanying Li, Mengbi Zhang, Min Liang, Aiqing Li
Background: The central nervous system plays a vital role in the development of hypertension, but the molecular regulatory mechanisms are not fully understood. This study aimed to explore signaling in the paraventricular nucleus (PVN) which might contribute to renal hypertension. Methods: Renal hypertension model was established by five-sixth nephrectomy operation (5/6Nx) in male Sprague Dawley rats. Ten weeks afterwards, they were random assigned to no treatment, or intracerebroventricular injection (ICV) with artificial cerebrospinal fluid, losartan [angiotensin II receptor type 1 (AT1R) antagonist], farnesylthiosalicylic acid (Ras inhibitor), PD98059 (MEK inhibitor), or SB203580 (p38 inhibitor) and Z-DEVD-FMK (caspase-3 inhibitor)...
2017: Frontiers in Physiology
https://www.readbyqxmd.com/read/28209091/hgf-induced-dna-synthesis-in-hepatocytes-is-suppressed-by-p38
#14
Monica Aasrum, Ingvild J Brusevold, Thoralf Christoffersen, G Hege Thoresen
Previous studies in rat hepatocytes have shown that the MEK/ERK, PI3K/Akt and p38 pathways are all involved in the activation of DNA synthesis by EGF and that sustained activation of MEK/ERK is required. Here, we show that although HGF stimulated DNA synthesis and activated signaling in the same manner as EGF, the contribution of the signaling pathways to the induction of DNA synthesis differed. While HGF-induced DNA synthesis was dependent on MEK/ERK, with no significant contribution from PI3K/Akt, p38 suppressed HGF-induced DNA synthesis...
December 2016: Growth Factors
https://www.readbyqxmd.com/read/28206960/an-autocrine-paracrine-circuit-of-growth-differentiation-factor-gdf-15-has-a-role-for-maintenance-of-breast-cancer-stem-like-cells
#15
Asako Sasahara, Kana Tominaga, Tatsunori Nishimura, Masao Yano, Etsuko Kiyokawa, Miki Noguchi, Masakuni Noguchi, Hajime Kanauchi, Toshihisa Ogawa, Hiroshi Minato, Keiichiro Tada, Yasuyuki Seto, Arinobu Tojo, Noriko Gotoh
Cancer stem cells are thought to be responsible for tumor growth, recurrence, and resistance to conventional cancer therapy. However, it is still unclear how they are maintained in tumor tissues. Here, we show that the growth differentiation factor 15 (GDF15), a member of the TGFβ family, may maintain cancer stem-like cells in breast cancer tissues by inducing its own expression in an autocrine/paracrine manner. We found that GDF15, but not TGFβ, increased tumor sphere formation in several breast cancer cell lines and patient-derived primary breast cancer cells...
February 11, 2017: Oncotarget
https://www.readbyqxmd.com/read/28203297/therapeutic-approach-to-treating-patients-with-braf-mutant-lung-cancer-latest-evidence-and-clinical-implications
#16
REVIEW
Adrianus J de Langen, Egbert F Smit
Lung adenocarcinoma is known for its high rate of somatic mutations and genomic rearrangements. The identification of epidermal growth factor receptor (EGFR) mutations and anaplastic lymphoma kinase (ALK) rearrangements that sensitize tumors to specific drugs has changed the therapeutic approach and prognosis in these molecularly-defined subgroups. Several other key genetic alterations have been identified, of which BRAF mutations are found in 4% of non-small cell lung cancer (NSCLC) cases. Targeted drugs against BRAF and downstream MEK were recently approved for the treatment of BRAF-positive melanoma and have entered clinical evaluation in NSCLC...
January 2017: Therapeutic Advances in Medical Oncology
https://www.readbyqxmd.com/read/28199980/pd-l1-up-regulation-in-melanoma-increases-disease-aggressiveness-and-is-mediated-through-mir-17-5p
#17
Valentina Audrito, Sara Serra, Aureliano Stingi, Francesca Orso, Federica Gaudino, Cinzia Bologna, Francesco Neri, Giulia Garaffo, Romina Nassini, Gianna Baroni, Eliana Rulli, Daniela Massi, Salvatore Oliviero, Roberto Piva, Daniela Taverna, Mario Mandalà, Silvia Deaglio
PD-L1 is expressed by a subset of patients with metastatic melanoma (MM) with an unfavorable outcome. Its expression is increased in cells resistant to BRAF or MEK inhibitors (BRAFi or MEKi). However, the function and regulation of expression of PD-L1 remain incompletely understood.After generating BRAFi- and MEKi-resistant cell lines, we observed marked up-regulation of PD-L1 expression. These cells were characterized by a common gene expression profile with up-regulation of genes involved in cell movement...
February 9, 2017: Oncotarget
https://www.readbyqxmd.com/read/28198367/usp9x-regulates-ets-1-ubiquitination-and-stability-to-control-nras-expression-and-tumorigenicity-in-melanoma
#18
Harish Potu, Luke F Peterson, Malathi Kandarpa, Anupama Pal, Hanshi Sun, Alison Durham, Paul W Harms, Peter C Hollenhorst, Ugur Eskiocak, Moshe Talpaz, Nicholas J Donato
ETS transcription factors are commonly deregulated in cancer by chromosomal translocation, overexpression or post-translational modification to induce gene expression programs essential in tumorigenicity. Targeted destruction of these proteins may have therapeutic impact. Here we report that Ets-1 destruction is regulated by the deubiquitinating enzyme, Usp9x, and has major impact on the tumorigenic program of metastatic melanoma. Ets-1 deubiquitination blocks its proteasomal destruction and enhances tumorigenicity, which could be reversed by Usp9x knockdown or inhibition...
February 15, 2017: Nature Communications
https://www.readbyqxmd.com/read/28197745/crosstalk-signaling-in-targeted-melanoma-therapy
#19
Svenja Meierjohann
Inhibition of the BRAF/MAPK pathway belongs to the standard therapies for patients with activating BRAF(V600E/K) mutations. However, even in well-responding tumors, anti-tumorigenic effect and clinical benefit are only transient, and the original tumors often relapse. This demonstrates that there are remaining residual tumors, which have withstood therapy-induced apoptosis and which have the potential to resume growth. Although BRAF mutant melanoma cells seem to depend on BRAF/MAPK signaling, the inhibition of this pathway triggers several events, which modulate the tumor as well as the tumor niche...
February 14, 2017: Cancer Metastasis Reviews
https://www.readbyqxmd.com/read/28194539/phase-i-trial-of-mek-1-2-inhibitor-pimasertib-combined-with-mtor-inhibitor-temsirolimus-in-patients-with-advanced-solid-tumors
#20
Monica Mita, Siqing Fu, Sarina Anne Piha-Paul, Filip Janku, Alain Mita, Ronald Natale, Wei Guo, Charles Zhao, Razelle Kurzrock, Aung Naing
Background Dual inhibition of activated MAPK and mTOR signaling pathways may enhance the antitumor efficacy of the MEK 1/2 inhibitor pimasertib and the mTOR inhibitor temsirolimus given in combination. Methods In this phase I study, patients with refractory advanced solid tumors (NCT01378377) received once-weekly temsirolimus plus once-daily oral pimasertib in 21-day cycles in a modified 3 + 3 dose-escalation design. The maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D) of pimasertib in combination with temsirolimus, safety and pharmacokinetics (PK) were investigated...
February 13, 2017: Investigational New Drugs
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