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https://www.readbyqxmd.com/read/29334371/cooperative-targeting-of-melanoma-heterogeneity-with-an-axl-antibody-drug-conjugate-and-braf-mek-inhibitors
#1
Julia Boshuizen, Louise A Koopman, Oscar Krijgsman, Aida Shahrabi, Elke Gresnigt- van den Heuvel, Maarten A Ligtenberg, David W Vredevoogd, Kristel Kemper, Thomas Kuilman, Ji-Ying Song, Nora Pencheva, Jens Thing Mortensen, Marnix Geukes Foppen, Elisa A Rozeman, Christian U Blank, Maarten L Janmaat, David Satijn, Esther C W Breij, Daniel S Peeper, Paul W H I Parren
Intratumor heterogeneity is a key factor contributing to therapeutic failure and, hence, cancer lethality. Heterogeneous tumors show partial therapy responses, allowing for the emergence of drug-resistant clones that often express high levels of the receptor tyrosine kinase AXL. In melanoma, AXL-high cells are resistant to MAPK pathway inhibitors, whereas AXL-low cells are sensitive to these inhibitors, rationalizing a differential therapeutic approach. We developed an antibody-drug conjugate, AXL-107-MMAE, comprising a human AXL antibody linked to the microtubule-disrupting agent monomethyl auristatin E...
January 15, 2018: Nature Medicine
https://www.readbyqxmd.com/read/29330049/the-histone-demethylase-phf8-promotes-adult-acute-lymphoblastic-leukemia-through-interaction-with-the-mek-erk-signaling-pathway
#2
Yue Fu, Yaling Yang, Xiaoming Wang, Xiaolin Yin, Minran Zhou, Siqi Wang, Lin Yang, Tao Huang, Man Xu, Chunyan Chen
Adult acute lymphoblastic leukemia (ALL) is a malignant disorder of lymphoid progenitor cells that is associated with a high risk of relapse and poor prognosis. Thus, novel pathogenic mechanisms and therapeutic targets need to be explored. Histone methylation is one of the most significant chromatin post-translational modifications. Here, we show that the histone demethylase PHF8 is highly expressed in a large number of ALL clinical specimens and that PHF8 expression is associated with ALL progression. PHF8 knockdown inhibits proliferation and promotes the apoptosis of ALL cells in vitro as well as attenuates tumor growth in vivo...
January 9, 2018: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/29329780/oncogenic-rac1-and-nras-drive-resistance-to-endoplasmic-reticulum-stress-through-mek-erk-signalling
#3
Michael D Bright, Paul A Clarke, Paul Workman, Faith E Davies
Cancer cells are able to survive under conditions that cause endoplasmic reticulum stress (ER-stress), and can adapt to this stress by upregulating cell-survival signalling pathways and down-regulating apoptotic pathways. The cellular response to ER-stress is controlled by the unfolded protein response (UPR). Small Rho family GTPases are linked to many cell responses including cell growth and apoptosis. In this study, we investigate the function of small GTPases in cell survival under ER-stress. Using siRNA screening we identify that RAC1 promotes cell survival under ER-stress in cells with an oncogenic N92I RAC1 mutation...
January 9, 2018: Cellular Signalling
https://www.readbyqxmd.com/read/29326440/braf-inhibition-upregulates-a-variety-of-receptor-tyrosine-kinases-and-their-downstream-effector-gab2-in-colorectal-cancer-cell-lines
#4
Ricarda Herr, Sebastian Halbach, Miriam Heizmann, Hauke Busch, Melanie Boerries, Tilman Brummer
BRAF mutations occur in ~10% of colorectal cancer (CRC) and are associated with poor prognosis. Inhibitors selective for the BRAFV600E oncoprotein, the most common BRAF mutant, elicit only poor response rates in BRAF-mutant CRC as single agents. This unresponsiveness was mechanistically attributed to the loss of negative feedbacks on the epidermal growth factor receptor (EGFR) and initiated clinical trials that combine BRAF (and MEK) inhibitors, either singly or in combination, with the anti-EGFR antibodies cetuximab or panitumumab...
January 12, 2018: Oncogene
https://www.readbyqxmd.com/read/29321660/activated-alk-signals-through-the-erk-etv5-ret-pathway-to-drive-neuroblastoma-oncogenesis
#5
Lucille Lopez-Delisle, Cécile Pierre-Eugène, Caroline Louis-Brennetot, Didier Surdez, Virginie Raynal, Sylvain Baulande, Valentina Boeva, Sandrine Grossetête-Lalami, Valérie Combaret, Michel Peuchmaur, Olivier Delattre, Isabelle Janoueix-Lerosey
Activating mutations of the ALK receptor occur in a subset of neuroblastoma tumors. We previously demonstrated that Alk mutations cooperate with MYCN overexpression to induce neuroblastoma in mice and identified Ret as being strongly upregulated in MYCN/Alkmut tumors. By a genetic approach in vivo, we now document an oncogenic cooperation between activated Ret and MYCN overexpression in neuroblastoma formation. We show that MYCN/RetM919T tumors exhibit histological features and expression profiles close to MYCN/Alkmut tumors...
January 11, 2018: Oncogene
https://www.readbyqxmd.com/read/29317674/spred2-deficiency-exacerbates-d-galactosamine-lipopolysaccharide-induced-acute-liver-injury-in-mice-via-increased-production-of-tnf%C3%AE
#6
Xu Yang, Masayoshi Fujisawa, Teizo Yoshimura, Toshiaki Ohara, Miwa Sato, Megumi Mino, Thar Htet San, Tong Gao, Steven L Kunkel, Akihiro Matsukawa
Acute liver injury (ALI) is characterized by hepatocyte damage and inflammation. In the present study, we examined whether the absence of Sprouty-related EVH1-domain-containing protein 2 (Spred2), a negative regulator of the Ras/Raf/ERK/MAPK pathway, influences ALI induced by D-galactosamine (D-GalN) and lipopolysaccharide (LPS). Compared to wild-type mice, Spred2-/- mice developed exacerbated liver injury represented by enhanced hepatocyte damage and inflammation. Enhanced ERK activation was observed in Spred2-/--livers, and the MEK/ERK inhibitor U0126 ameliorated ALI...
January 9, 2018: Scientific Reports
https://www.readbyqxmd.com/read/29317148/discovery-of-ebi-1051-a-novel-and-orally-efficacious-mek-inhibitor-with-benzofuran-scaffold
#7
Biao Lu, Song Huang, Jingsong Cao, Qiyue Hu, Ru Shen, Hong Wan, Dan Wang, Jijun Yuan, Lei Zhang, Jiayin Zhang, Minsheng Zhang, Weikang Tao, Lianshan Zhang
A novel series of benzodihydrofuran derivatives was developed as potent MEK inhibitors through scaffold hopping based on known clinical compounds. Further SAR exploration and optimization led to another benzofuran series with good oral bioavailability in rats. One of the compounds EBI-1051 (28d) demonstrated excellent in vivo efficacy in colo-205 tumor xenograft models in mouse and is suitable for pre-clinical development studies for the treatment of melanoma and MEK associated cancers. Compared to AZD6244, EBI-1051 showed superior potency in some cancer cell lines such as colon-205, A549 and MDA-MB-231...
December 20, 2017: Bioorganic & Medicinal Chemistry
https://www.readbyqxmd.com/read/29315345/identification-and-functional-analysis-of-sox10-phosphorylation-sites-in-melanoma
#8
Julia C Cronin, Stacie K Loftus, Laura L Baxter, Steve Swatkoski, Marjan Gucek, William J Pavan
The transcription factor SOX10 plays an important role in vertebrate neural crest development, including the establishment and maintenance of the melanocyte lineage. SOX10 is also highly expressed in melanoma tumors, and SOX10 expression increases with tumor progression. The suppression of SOX10 in melanoma cells activates TGF-β signaling and can promote resistance to BRAF and MEK inhibitors. Since resistance to BRAF/MEK inhibitors is seen in the majority of melanoma patients, there is an immediate need to assess the underlying biology that mediates resistance and to identify new targets for combinatorial therapeutic approaches...
2018: PloS One
https://www.readbyqxmd.com/read/29315294/the-oral-vegf-receptor-tyrosine-kinase-inhibitor-pazopanib-in-combination-with-the-mek-inhibitor-trametinib-in-advanced-cholangiocarcinoma
#9
Rachna T Shroff, Mark Yarchoan, Ashley O'Connor, Denise Gallagher, Marianna L Zahurak, Gary Rosner, Chimela Ohaji, Susan Sartorius-Mergenthaler, Rose Parkinson, Vivek Subbiah, Ralph Zinner, Nilofer S Azad
This corrects the article DOI: 10.1038/bjc.2017.119.
January 9, 2018: British Journal of Cancer
https://www.readbyqxmd.com/read/29312543/dual-targeting-of-her3-and-mek-may-overcome-her3-dependent-drug-resistance-of-colon-cancers
#10
Giulia Bon, Rossella Loria, Carla Azzurra Amoreo, Alessandra Verdina, Isabella Sperduti, Arianna Mastrofrancesco, Silvia Soddu, Maria Grazia Diodoro, Marcella Mottolese, Matilde Todaro, Giorgio Stassi, Michele Milella, Ruggero De Maria, Rita Falcioni
Although the medical treatment of colorectal cancer has evolved greatly in the last years, a significant portion of early-stage patients develops recurrence after therapies. The current clinical trials are directed to evaluate new drug combinations and treatment schedules. By the use of patient-derived or established colon cancer cell lines, we found that the tyrosine kinase receptor HER3 is involved in the mechanisms of resistance to therapies. In agreement, the immunohistochemical analysis of total and phospho-HER3 expression in 185 colorectal cancer specimens revealed a significant correlation with lower disease-free survival...
December 12, 2017: Oncotarget
https://www.readbyqxmd.com/read/29311225/keeping-tumors-out-of-the-mapk-fitness-zone
#11
David F Stern
Greatest fitness of tumor cell subclones in patients undergoing MAPK-targeting therapies requires just-right levels of MAPK pathway signaling. New therapeutic approaches induce tumor cell death by intensifying MAPK signaling induced by inhibitor withdrawal in combination with DNA damage, or prevent selection of resistant clones with a steep fitness barrier imposed by triple combination of BRAF, MEK, and ERK inhibitors. Cancer Discov; 8(1); 20-3. ©2018 AACRSee related article by Hong et al., p. 74.
January 2018: Cancer Discovery
https://www.readbyqxmd.com/read/29310804/the-cytoskeletal-network-regulates-expression-of-the-profibrotic-genes-pai-1-and-ctgf-in-vascular-smooth-muscle-cells
#12
Rohan Samarakoon, Paul J Higgins
Vascular smooth muscle cells (VSMCs) are subject to changing hemodynamic stimuli that alter cytoskeletal dynamics, cellular architecture, and structure-associated signal transduction. Tensional stress, force application, and structural perturbations are sensed by VSMCs and impact the physiological as well as pathophysiological responses of the vasculature. Microtubule-targeting drugs provide useful tools to analyze cytoskeletal-associated signaling pathways and their linkages to pathological outcomes. Architecture-based controls on a subset of profibrotic genes commonly expressed in vascular disease are highlighted by their frequent induction in mechanically manipulated cells and with associated changes in cytoskeletal dynamics...
2018: Advances in Pharmacology
https://www.readbyqxmd.com/read/29309927/glycogen-synthase-kinases-moonlighting-proteins-with-theranostic-potential-in-cancer
#13
REVIEW
Siddavaram Nagini, Josephraj Sophia, Rajakishore Mishra
Glycogen synthase kinase-3 (GSK-3), a serine/threonine kinase is an archetypal multifunctional moonlighting protein involved in diverse cellular processes including metabolism, insulin signaling, proliferation, differentiation, apoptosis, neuronal function and embryonic development. The two known isoforms, GSK-3α and GSK-3β that undergo activation/inactivation by post-translational, site-specific phosphorylation incorporate a vast number of substrates in their repertoire. Dysregulation of GSK-3 has been linked to diverse disease entities including cancer...
January 5, 2018: Seminars in Cancer Biology
https://www.readbyqxmd.com/read/29309612/nicotinamide-phosphoribosyltransferase-nampt-as-a-therapeutic-target-in-braf-mutated-metastatic-melanoma
#14
Valentina Audrito, Antonella Managò, Sofia La Vecchia, Federica Zamporlini, Nicoletta Vitale, Gianna Baroni, Simona Cignetto, Sara Serra, Cinzia Bologna, Aureliano Stingi, Francesca Arruga, Tiziana Vaisitti, Daniela Massi, Mario Mandalà, Nadia Raffaelli, Silvia Deaglio
Background: One of the effects of oncogenic signaling is metabolic reprogramming of tumor cells to support anabolic growth, opening the way to therapeutic targeting of metabolic pathways. Methods: We studied NAD biosynthesis in BRAF inhibitor (BRAFi)-resistant (BiR) melanoma cell lines. Data in cell lines were confirmed by immunohistochemistry in biopsies from 17 patients with metastatic melanoma (MM) before and after the acquisition of resistance to BRAFi. Therapeutic potential of NAD biosynthesis inhibitors was determined by invitro monitoring cell growth and death and in mouse xenograft models...
March 1, 2018: Journal of the National Cancer Institute
https://www.readbyqxmd.com/read/29307569/is-nanoclustering-essential-for-all-oncogenic-kras-pathways-can-it-explain-why-wild-type-kras-can-inhibit-its-oncogenic-variant
#15
REVIEW
Ruth Nussinov, Chung-Jung Tsai, Hyunbum Jang
Membrane-anchored oncogenic KRas can dimerize, form nanoclusters, and signal through the MAPK (Raf/MEK/ERK) and PI3Kα/Akt/mTOR. Both pathways are needed in KRAS-driven proliferation. Here we ask: Is oncogenic KRas nanoclustering (or dimerization) essential for all KRas signaling pathways? Raf kinase domain dimerization, thus MAPK activation, requires KRas nanoclusters. By contrast, the PI3Kα heterodimer acts as a monomeric unit; thus, does PI3Kα activation and PI3Kα/Akt/mTOR signaling require nanoclustering? Further, calmodulin binds only to oncogenic KRas4B...
January 4, 2018: Seminars in Cancer Biology
https://www.readbyqxmd.com/read/29306208/alpha-2-dihydroxy-4-4-dimethoxydihydrochalcone-inhibits-cell-proliferation-invasion-and-migration-in-gastric-cancer-in-part-via-autophagy
#16
Boshun Wan, Junqiu Zhu, Qing Chang, Haihua Zhou, Zhan Shi, Li Min, YueJiao Cai, Honggeng Guan
Gastric cancer is a leading cause of mortality worldwide. Alpha, 2'-dihydroxy-4,4'-dimethoxydihydrochalcone is a type of limonoid mainly isolated from Cedrela odorata (Meliaceae) that has been shown to suppress cell proliferation in several human carcinoma cell lines. In this study, we investigated the anti-cancer ability of alpha, 2'-dihydroxy-4,4'-dimethoxydihydrochalcone and its underlying mechanism in MKN45 cells. Alpha, 2'-dihydroxy-4,4'-dimethoxydihydrochalcone induced excess reactive oxygen species (ROS) accumulation...
January 2, 2018: Biomedicine & Pharmacotherapy, Biomédecine & Pharmacothérapie
https://www.readbyqxmd.com/read/29305928/anti-proliferative-activity-of-biochanin-a-in-human-osteosarcoma-cells-via-mitochondrial-involved-apoptosis
#17
Yen-Nien Hsu, Huey-Wen Shyu, Tsui-Wen Hu, Jou-Pei Yeh, Ya-Wen Lin, Ling-Yi Lee, Yao-Tsung Yeh, Hong-Ying Dai, Daw-Shyong Perng, Shu-Hui Su, Yu-Hsuan Huang, Shu-Jem Su
Biochanin A is a major isoflavone in red clover and a potent chemopreventive agent against cancer. However, the effects of biochanin A on human osteosarcoma cells have never been clarified. This study investigated the anti-proliferative potential of biochanin A in osteosarcoma cells. The results indicate that biochanin A inhibited cell growth and colony formation in a dose-dependent manner with a minimal toxicity to normal cells. The combination of doxorubicin and biochanin A could synergistically inhibit osteosarcoma cell growth...
January 3, 2018: Food and Chemical Toxicology
https://www.readbyqxmd.com/read/29298720/ccat2-is-an-oncogenic-long-non-coding-rna-in-pancreatic-ductal-adenocarcinoma
#18
Yi Cai, Xiaomei Li, Peng Shen, Dong Zhang
BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is highly aggressive with poor prognosis. Long non-coding RNAs (lncRNAs), a group of non-coding RNAs, play important roles in the progression of PDAC. This study aimed to investigate the potential involvement of lncRNA CCAT2 in PDAC tumorigenesis. METHODS: Expression of CCAT2 was detected by quantitative real-time PCR (qRT-PCR) in 80 human PDAC tissues and three PDAC cell lines. The effects of CCAT2 silencing in PANC-1 cells on cell proliferation and invasion were studied using MTT assay and transwell assay, respectively...
January 3, 2018: Biological Research
https://www.readbyqxmd.com/read/29296217/pharmacologic-characterization-of-shr8443-a-novel-dual-inhibitor-of-phosphatidylinositol-3-kinase-and-mammalian-target-of-rapamycin
#19
Chengying Xie, Xiangling Chen, Mingyue Zheng, Xiaohong Liu, Hongbin Wang, Liguang Lou
Dysregulation of the phosphatidylinositol 3-kinase (PI3K) pathway occurs frequently in human cancer and contributes to resistance to antitumor therapy. Inhibition of key signaling proteins in this pathway therefore represents an attractive targeting strategy for cancer therapy. Here, we show that SHR8443, an imidazo [4,5-c] quinoline derivative, inhibited mammalian target of rapamycin (mTOR) kinase and PI3K, especially PI3Kα/δ/γ isoforms with picomolar potency, by binding to the ATP subunits of the respective enzymes...
December 8, 2017: Oncotarget
https://www.readbyqxmd.com/read/29296181/correlation-between-mek-signature-and-ras-gene-alteration-in-advanced-gastric-cancer
#20
Soomin Ahn, Roz Brant, Alan Sharpe, Jonathan R Dry, Darren R Hodgson, Elaine Kilgour, Kyung Kim, Seung Tae Kim, Se Hoon Park, Won Ki Kang, Kyoung-Mee Kim, Jeeyun Lee
MEK inhibitor (selumetinib) is a potent, orally active inhibitor of MAPK/ERK pathway. It is important to develop an accurate and robust method indicative of RAS pathway activity to stratify potential patients who can benefit from selumetinib treatment in gastric cancer (GC). First, we surveyed the sensitivity to selumetinib in a panel of 22 GC cell lines and correlated with MEK signature to selumetinib sensitivity. Next, we analyzed MEK signature via nanostring assay in two Asian cohorts using clinical samples (n = 218) and then performed a correlative analysis with MEK signature status and KRAS genotype in GC...
December 8, 2017: Oncotarget
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