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https://www.readbyqxmd.com/read/27811184/coupling-an-eml4-alk-centric-interactome-with-rna-interference-identifies-sensitizers-to-alk-inhibitors
#1
Guolin Zhang, Hannah Scarborough, Jihye Kim, Andrii I Rozhok, Yian Ann Chen, Xiaohui Zhang, Lanxi Song, Yun Bai, Bin Fang, Richard Z Liu, John Koomen, Aik Choon Tan, James Degregori, Eric B Haura
Patients with lung cancers harboring anaplastic lymphoma kinase (ALK) gene fusions benefit from treatment with ALK inhibitors, but acquired resistance inevitably arises. A better understanding of proximal ALK signaling mechanisms may identify sensitizers to ALK inhibitors that disrupt the balance between prosurvival and proapoptotic effector signals. Using affinity purification coupled with mass spectrometry in an ALK fusion lung cancer cell line (H3122), we generated an ALK signaling network and investigated signaling activity using tyrosine phosphoproteomics...
October 18, 2016: Science Signaling
https://www.readbyqxmd.com/read/27664399/in-silico-prediction-and-in-vitro-and-in-vivo-validation-of-acaricide-fluazuron-as-a-potential-inhibitor-of-fgfr3-and-a-candidate-anticancer-drug-for-bladder-carcinoma
#2
Kunbin Ke, Hongjian Li, Hong Yao, Xi-Nan Shi, Chao Dong, Ying Zhu, Xu Liu, Ling Li, Kwong-Sak Leung, Man-Hon Wong, Xiao-Dong Liu, Hsiang-Fu Kung, Marie Chia-Mi Lin
Bladder carcinoma (BC) is the 9(th) most common cause of cancer worldwide. Surgical resection and conventional chemotherapy and radiotherapy will ultimately fail due to tumor recurrence and resistance. Thus, the development of novel treatment is urgently needed. Fibroblast growth factor receptor 3 (FGFR3) is an important and well-established target for BC treatment. In this study, we utilized the free and open-source protein-ligand docking software idock to prospectively identify potential inhibitors of FGFR3 from 3167 worldwide approved small-molecule drugs using a repositioning strategy...
September 24, 2016: Chemical Biology & Drug Design
https://www.readbyqxmd.com/read/27615514/proximity-labeling-reveals-molecular-determinants-of-fgfr4-endosomal-transport
#3
Ellen Margrethe Haugsten, Vigdis Sørensen, Michaela Kunova Bosakova, Gustavo Antonio de Souza, Pavel Krejci, Antoni Wiedlocha, Jørgen Wesche
The fibroblast growth factor receptors (FGFRs) are important oncogenes promoting tumor progression in many types of cancer, such as breast, bladder, and lung cancer as well as multiple myeloma and rhabdomyosarcoma. However, little is known about how these receptors are internalized and down-regulated in cells. We have here applied proximity biotin labeling to identify proteins involved in FGFR4 signaling and trafficking. For this purpose we fused a mutated biotin ligase, BirA*, to the C-terminal tail of FGFR4 (FGFR4-BirA*) and the fusion protein was stably expressed in U2OS cells...
October 7, 2016: Journal of Proteome Research
https://www.readbyqxmd.com/read/27550940/identification-of-pharmacodynamic-transcript-biomarkers-in-response-to-fgfr-inhibition-by-azd4547
#4
Oona Delpuech, Claire Rooney, Lorraine Mooney, Dawn Baker, Robert Shaw, Michael Dymond, Dennis Wang, Pei Zhang, Sarah Cross, Margaret H Veldman-Jones, Joanne Wilson, Barry R Davies, Jonathan R Dry, Elaine Kilgour, Paul D Smith
The challenge of developing effective pharmacodynamic biomarkers for pre-clinical and clinical testing of FGFR signalling inhibition is significant. Assays that rely on the measurement of phospho-protein epitopes can be limited by the availability of effective antibody detection reagents. Transcript profiling enables accurate quantification of many biomarkers and provides a broader representation of pathway modulation. To identify dynamic transcript biomarkers of FGFR signalling inhibition by AZD4547, a potent inhibitor of FGF receptor 1, 2 and 3, a gene expression profiling study was performed in FGFR2 amplified, drug sensitive tumour cell lines...
August 22, 2016: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/27533459/mir-4653-3p-and-its-target-gene-frs2-are-prognostic-biomarkers-for-hormone-receptor-positive-breast-cancer-patients-receiving-tamoxifen-as-adjuvant-endocrine-therapy
#5
XiaoRong Zhong, GuiQin Xie, Zhang Zhang, Zhu Wang, Yu Wang, YanPing Wang, Yan Qiu, Li Li, Hong Bu, JiaYuan Li, Hong Zheng
Long-term tamoxifen treatment significantly improves the survival of hormone receptor-positive (HR+) breast cancer (BC) patients. However, tamoxifen resistance remains a challenge. We aimed to identify prognostic biomarkers for tamoxifen resistance and reveal the underlying mechanism. From March 2001 to September 2013, 400 HR+ BC women (stage I~III) were treated with adjuvant tamoxifen for 5 years or until relapse in West China Hospital. We included a discovery set of 6 patients who were refractory to tamoxifen, and a validation cohort of 88 patients including 35 cases with relapse...
August 13, 2016: Oncotarget
https://www.readbyqxmd.com/read/27503856/unravelling-the-mechanism-of-trka-induced-cell-death-by-macropinocytosis-in-medulloblastoma-daoy-cells
#6
Chunhui Li, James I S MacDonald, Asghar Talebian, Jennifer Leuenberger, Claudia Seah, Stephen H Pasternak, Stephen W Michnick, Susan O Meakin
Macropinocytosis is a normal cellular process by which cells internalize extracellular fluids and nutrients from their environment and is one strategy that Ras-transformed pancreatic cancer cells use to increase uptake of amino acids to meet the needs of rapid growth. Paradoxically, in non-Ras transformed medulloblastoma brain tumors, we have shown that expression and activation of the receptor tyrosine kinase TrkA overactivates macropinocytosis, resulting in the catastrophic disintegration of the cell membrane and in tumor cell death...
October 15, 2016: Molecular and Cellular Biology
https://www.readbyqxmd.com/read/27409346/preclinical-evaluation-of-potential-therapeutic-targets-in-dedifferentiated-liposarcoma
#7
Robert Hanes, Iwona Grad, Susanne Lorenz, Eva W Stratford, Else Munthe, Chilamakuri Chandra Sekhar Reddy, Leonardo A Meza-Zepeda, Ola Myklebost
Sarcomas are rare cancers with limited treatment options. Patients are generally treated by chemotherapy and/or radiotherapy in combination with surgery, and would benefit from new personalized approaches. In this study we demonstrate the potential of combining personal genomic characterization of patient tumors to identify targetable mutations with in vitro testing of specific drugs in patient-derived cell lines. We have analyzed three metastases from a patient with high-grade metastatic dedifferentiated liposarcoma (DDLPS) by exome and transcriptome sequencing as well as DNA copy number analysis...
July 9, 2016: Oncotarget
https://www.readbyqxmd.com/read/27392325/key-roles-of-emt-for-adaptive-resistance-to-mek-inhibitor-in-kras-mutant-lung-cancer
#8
Hidenori Kitai, Hiromichi Ebi
KRAS is frequently mutated in a variety of cancers including lung cancer. Whereas the mitogen-activated protein kinase (MAPK) is a well-known effector pathway of KRAS, blocking this pathway with MEK inhibitors is relatively ineffective. One major contributor to limited efficacy is attributed to the reactivation of MAPK signal following MEK inhibition by multiple feedback mechanisms. In a recent study, we have identified that epithelial-to-mesenchymal transition defines feedback activation of receptor tyrosine kinase signaling following MEK inhibition in KRAS mutant lung cancer...
July 8, 2016: Small GTPases
https://www.readbyqxmd.com/read/27338794/a-combinatorial-strategy-for-treating-kras-mutant-lung-cancer
#9
Eusebio Manchado, Susann Weissmueller, John P Morris, Chi-Chao Chen, Ramona Wullenkord, Amaia Lujambio, Elisa de Stanchina, John T Poirier, Justin F Gainor, Ryan B Corcoran, Jeffrey A Engelman, Charles M Rudin, Neal Rosen, Scott W Lowe
Therapeutic targeting of KRAS-mutant lung adenocarcinoma represents a major goal of clinical oncology. KRAS itself has proved difficult to inhibit, and the effectiveness of agents that target key KRAS effectors has been thwarted by activation of compensatory or parallel pathways that limit their efficacy as single agents. Here we take a systematic approach towards identifying combination targets for trametinib, a MEK inhibitor approved by the US Food and Drug Administration, which acts downstream of KRAS to suppress signalling through the mitogen-activated protein kinase (MAPK) cascade...
June 30, 2016: Nature
https://www.readbyqxmd.com/read/27189169/smooth-muscle-fgf-tgf%C3%AE-cross-talk-regulates-atherosclerosis-progression
#10
Pei-Yu Chen, Lingfeng Qin, Guangxin Li, George Tellides, Michael Simons
The conversion of vascular smooth muscle cells (SMCs) from contractile to proliferative phenotype is thought to play an important role in atherosclerosis. However, the contribution of this process to plaque growth has never been fully defined. In this study, we show that activation of SMC TGFβ signaling, achieved by suppression of SMC fibroblast growth factor (FGF) signaling input, induces their conversion to a contractile phenotype and dramatically reduces atherosclerotic plaque size. The FGF/TGFβ signaling cross talk was observed in vitro and in vivo In vitro, inhibition of FGF signaling increased TGFβ activity, thereby promoting smooth muscle differentiation and decreasing proliferation...
July 1, 2016: EMBO Molecular Medicine
https://www.readbyqxmd.com/read/27141054/fibroblast-growth-factor-receptor-dependent-and-independent-paracrine-signaling-by-sunitinib-resistant-renal-cell-carcinoma
#11
Tram Anh Tran, Hon Sing Leong, Andrea Pavia-Jimenez, Slavic Fedyshyn, Juan Yang, Blanka Kucejova, Sharanya Sivanand, Patrick Spence, Xian-Jin Xie, Samuel Peña-Llopis, Nicholas Power, James Brugarolas
Antiangiogenic therapies, such as sunitinib, have revolutionized renal cell carcinoma (RCC) treatment. However, a precarious understanding of how resistance emerges and a lack of tractable experimental systems hinder progress. We evaluated the potential of primary RCC cultures (derived from tumors and tumor grafts) to signal to endothelial cells (EC) and fibroblasts in vitro and to stimulate angiogenesis ex vivo in chorioallantoic membrane (CAM) assays. From 65 patients, 27 primary cultures, including several from patients with sunitinib-resistant RCC, were established...
July 1, 2016: Molecular and Cellular Biology
https://www.readbyqxmd.com/read/27136102/targeting-fgfr2-with-alofanib-rpt835-shows-potent-activity-in-tumour-models
#12
Ilya Tsimafeyeu, John Ludes-Meyers, Evgenia Stepanova, Frits Daeyaert, Dmitry Kochenkov, Jean-Baptiste Joose, Eliso Solomko, Koen Van Akene, Nina Peretolchina, Wei Yin, Oxana Ryabaya, Mikhail Byakhov, Sergei Tjulandin
Alofanib (RPT835) is a novel selective allosteric inhibitor of fibroblast growth factor receptor 2 (FGFR2). We showed previously that alofanib could bind to the extracellular domain of FGFR2 and has an inhibitory effect on FGF2-induced phoshphorylation of FRS2α. In the present study, we further showed that alofanib inhibited phosphorylation of FRS2α with the half maximal inhibitory concentration (IC50) values of 7 and 9 nmol/l in cancer cells expressing different FGFR2 isoforms. In a panel of four cell lines representing several tumour types (triple-negative breast cancer, melanoma, and ovarian cancer), alofanib inhibited FGF-mediated proliferation with 50% growth inhibition (GI50) values of 16-370 nmol/l...
July 2016: European Journal of Cancer
https://www.readbyqxmd.com/read/27029060/trichlorobenzene-substituted-azaaryl-compounds-as-novel-fgfr-inhibitors-exhibiting-potent-antitumor-activity-in-bladder-cancer-cells-in-vitro-and-in-vivo
#13
Chun-Han Chen, Yi-Min Liu, Shiow-Lin Pan, Yun-Ru Liu, Jing-Ping Liou, Yun Yen
In the present study, we examined the antitumor activity of a series of trichlorobenzene-substituted azaaryl compounds and identified MPT0L145 as a novel FGFR inhibitor with better selectivity for FGFR1, 2 and 3. It was preferentially effective in FGFR-activated cancer cells, including bladder cancer cell lines expressing FGFR3-TACC3 fusion proteins (RT-112, RT-4). MPT0L145 decreased the phosphorylation of FGFR1, FGFR3 and their downstream proteins (FRS2, ERK and Akt). Mechanistically, cDNA microarray analysis revealed that MPT0L145 decreased genes associated cell cycle progression, and increased genes associated with autophagy pathway...
May 3, 2016: Oncotarget
https://www.readbyqxmd.com/read/26969380/sinapine-reverses-multi-drug-resistance-in-mcf-7-dox-cancer-cells-by-downregulating-fgfr4-frs2%C3%AE-erk1-2-pathway-mediated-nf-%C3%AE%C2%BAb-activation
#14
Ying Guo, Yuanyuan Ding, Tao Zhang, Hongli An
BACKGROUND: Sinapine, an alkaloid derived from seeds of the cruciferous species, shows favorable biological properties, such as antioxidant and radio-protective activities. The inhibitory effect of sinapine on acquired chemoresistance in tumor cells and the underlying molecular mechanisms remain unknown. AIM: We examined the effect of sinapine on reversal of chemoresistance in Michigan Cancer Foundation 7 (MCF-7)/dox breast cancer cells. RESULTS: Combination treatment with sinapine and doxorubicin synergistically increased the cytotoxicity of doxorubicin in MCF-7/dox cells, as shown using a cell apoptosis assay...
March 15, 2016: Phytomedicine: International Journal of Phytotherapy and Phytopharmacology
https://www.readbyqxmd.com/read/26942290/mosaic-activating-mutations-in-fgfr1-cause-encephalocraniocutaneous-lipomatosis
#15
James T Bennett, Tiong Yang Tan, Diana Alcantara, Martine Tétrault, Andrew E Timms, Dana Jensen, Sarah Collins, Malgorzata J M Nowaczyk, Marjorie J Lindhurst, Katherine M Christensen, Stephen R Braddock, Heather Brandling-Bennett, Raoul C M Hennekam, Brian Chung, Anna Lehman, John Su, SuYuen Ng, David J Amor, Jacek Majewski, Les G Biesecker, Kym M Boycott, William B Dobyns, Mark O'Driscoll, Ute Moog, Laura M McDonell
Encephalocraniocutaneous lipomatosis (ECCL) is a sporadic condition characterized by ocular, cutaneous, and central nervous system anomalies. Key clinical features include a well-demarcated hairless fatty nevus on the scalp, benign ocular tumors, and central nervous system lipomas. Seizures, spasticity, and intellectual disability can be present, although affected individuals without seizures and with normal intellect have also been reported. Given the patchy and asymmetric nature of the malformations, ECCL has been hypothesized to be due to a post-zygotic, mosaic mutation...
March 3, 2016: American Journal of Human Genetics
https://www.readbyqxmd.com/read/26934577/exome-sequencing-of-oral-squamous-cell-carcinoma-in-users-of-arabian-snuff-reveals-novel-candidates-for-driver-genes
#16
Nezar Noor Al-Hebshi, Shiyong Li, Akram Thabet Nasher, Maged El-Setouhy, Rashad Alsanosi, Jan Blancato, Christopher Loffredo
The study sought to identify genetic aberrations driving oral squamous cell carcinoma (OSCC) development among users of shammah, an Arabian preparation of smokeless tobacco. Twenty archival OSCC samples, 15 of which with a history of shammah exposure, were whole-exome sequenced at an average depth of 127×. Somatic mutations were identified using a novel, matched controls-independent filtration algorithm. CODEX and Exomedepth coupled with a novel, Database of Genomic Variant-based filter were employed to call somatic gene-copy number variations...
July 15, 2016: International Journal of Cancer. Journal International du Cancer
https://www.readbyqxmd.com/read/26804240/estrogen-regulates-excitatory-amino-acid-carrier-1-eaac1-expression-through-sphingosine-kinase-1-sphk1-transacting-fgfr-mediated-erk-signaling-in-rat-c6-astroglial-cells
#17
C Huang, P Yuan, J Wu, J Huang
Excitatory amino acid carrier 1 (EAAC1) is one important subtype of the excitatory amino acid transporters (EAATs), and its absence can increase the vulnerability to oxidative stress in neural tissue. Enhanced expression of EAAC1 can provide neuroprotection in multiple disorders, including ischemia and multiple sclerosis. However, the mechanism regulating EAAC1 expression is not fully understood. Using rat C6 astroglial cells, which specifically express EAAC1, we found that 17β-estradiol (E2) and (±)-1-[(3aR(∗),4S(∗),9bS(∗))-4-(6-bromo-1,3-benzodioxol-5-yl)-3a,4,5,9b-tetrahydro-3H-cyclopenta[c]quinolin-8-yl]-ethanone (G1), an agonist of the G-protein-coupled estrogen receptor (GPR30), strongly increased EAAC1 protein levels and protected cells from hydrogen peroxide (H2O2) toxicity...
April 5, 2016: Neuroscience
https://www.readbyqxmd.com/read/26758997/association-between-insulin-resistance-and-impairment-of-fgf21-signal-transduction-in-skeletal-muscles
#18
Ja Young Jeon, Sung-E Choi, Eun Suk Ha, Tae Ho Kim, Jong Gab Jung, Seung Jin Han, Hae Jin Kim, Dae Jung Kim, Yup Kang, Kwan-Woo Lee
Fibroblast growth factor (FGF) 21, was identified as a potent metabolic regulator of glucose and lipid metabolism. We investigated whether the levels and signalings of FGF21 changed in the skeletal muscle of type 2 diabetes mellitus (T2DM) patients, participants with impaired glucose tolerance (IGT), human skeletal muscle myotubes (HSMMs) under insulin-resistant conditions, and mice with diet-induced obesity (DIO). A percutaneous biopsy sample of the vastus lateralis muscle of T2DM patients, IGT subjects, and participants with normal glucose tolerance was obtained and the levels and signalings of FGF21 were assessed...
July 2016: Endocrine
https://www.readbyqxmd.com/read/26574622/antitumor-effects-and-molecular-mechanisms-of-ponatinib-on-endometrial-cancer-cells-harboring-activating-fgfr2-mutations
#19
Do-Hee Kim, Yeonui Kwak, Nam Doo Kim, Taebo Sim
Aberrant mutational activation of FGFR2 is associated with endometrial cancers (ECs). AP24534 (ponatinib) currently undergoing clinical trials has been known to be an orally available multi-targeted tyrosine kinase inhibitor. Our biochemical kinase assay showed that AP24534 is potent against wild-type FGFR1-4 and 5 mutant FGFRs (V561M-FGFR1, N549H-FGFR2, K650E-FGFR3, G697C-FGFR3, N535K-FGFR4) and possesses the strongest kinase-inhibitory activity on N549H-FGFR2 (IC50 of 0.5 nM) among all FGFRs tested. We therefore investigated the effects of AP24534 on endometrial cancer cells harboring activating FGFR2 mutations and explored the underlying molecular mechanisms...
2016: Cancer Biology & Therapy
https://www.readbyqxmd.com/read/26556626/peptidomimetic-suppresses-proliferation-and-invasion-of-gastric-cancer-cells-by-fibroblast-growth-factor-2-signaling-cascade-blockage
#20
Wulan Li, Xiaojing Du, Qiuxiang Chen, Yanting Kang, Chaochao Xu, Lei Fan, Hui Ye, Shilong Ying, Lingyi Shi, Rong Jin, Jianzhang Wu, Guang Liang, Xiaokun Li
Fibroblast growth factor 2 (FGF2) is closely involved in a variety of tumors, including gastric cancer (GC). FGF2 inhibitors exert good antitumor activity, but no FGF2 inhibitor has been employed for clinical use. To obtain a low-toxicity, stable peptidomimetic (called P29) target to FGF2, the affinity between P29 and FGF2 was detected by surface plasmon resonance. The stability of P29 was measured by high performance liquid chromatography. MTT assay and transwell assay were used to access the proliferative and invasive ability of GC cells, respectively...
March 2016: Anti-cancer Drugs
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