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https://www.readbyqxmd.com/read/28558797/expression-of-signaling-adaptor-proteins-predicts-poor-prognosis-in-pancreatic-ductal-adenocarcinoma
#1
Lili Wang, Junliang Lu, Huanwen Wu, Li Wang, Xiaolong Liang, Zhiyong Liang, Tonghua Liu
BACKGROUND: Adaptor proteins bridge the gap between cell surface receptors and their downstream signaling elements. The clinicopathological and prognostic values of adaptor proteins remain poorly understood. The purpose of the present study was to explore the expression and prognostic value of three adaptor proteins: GRB2-associated binding protein 2 (GAB2), CRK-like protein (CRKL) and fibroblast growth factor receptor substrate 2 (FRS2) in pancreatic ductal adenocarcinoma (PDAC). METHODS: The expression of GAB2, CRKL, and FRS2 in 77 formalin fixed paraffin embedded (FFPE) samples from 77 PDAC patients, along with three paired fresh PDAC and matched normal tissues from 3 PDAC patients was analyzed by immunohistochemistry and western blot, respectively...
May 30, 2017: Diagnostic Pathology
https://www.readbyqxmd.com/read/28483978/fgf-dependent-context-driven-role-for-frs-adapters-in-the-early-telencephalon
#2
Sayan Nandi, Grigoriy Gutin, Christopher A Blackwood, Nachiket G Kamatkar, Kyung W Lee, Gordon Fishell, Fen Wang, Mitchell Goldfarb, Jean M Hébert
FGF signaling, an important component of intercellular communication, is required in many tissues throughout development to promote diverse cellular processes. Whether FGF receptors (FGFRs) accomplish such varied tasks in part by activating different intracellular transducers in different contexts remains unclear. Here, we used the developing mouse telencephalon as an example to study the role of the FRS adapters FRS2 and FRS3 in mediating the functions of FGFRs. Using tissue-specific and germline mutants, we examined the requirement of Frs genes in two FGFR-dependent processes...
June 7, 2017: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
https://www.readbyqxmd.com/read/28473845/pancreatic-islet-protein-complexes-and-their-dysregulation-in-type-2-diabetes
#3
Helle Krogh Pedersen, Valborg Gudmundsdottir, Søren Brunak
Type 2 diabetes (T2D) is a complex disease that involves multiple genes. Numerous risk loci have already been associated with T2D, although many susceptibility genes remain to be identified given heritability estimates. Systems biology approaches hold potential for discovering novel T2D genes by considering their biological context, such as tissue-specific protein interaction partners. Pancreatic islets are a key T2D tissue and many of the known genetic risk variants lead to impaired islet function, hence a better understanding of the islet-specific dysregulation in the disease-state is essential to unveil the full potential of person-specific profiles...
2017: Frontiers in Genetics
https://www.readbyqxmd.com/read/28445992/interaction-between-the-estrogen-receptor-and-fibroblast-growth-factor-receptor-pathways-in-non-small-cell-lung-cancer
#4
Jill M Siegfried, Mariya Farooqui, Natalie J Rothenberger, Sanja Dacic, Laura P Stabile
The estrogen receptor (ER) promotes non-small cell lung cancer (NSCLC) proliferation. Since fibroblast growth factors (FGFs) are known regulators of stem cell markers in ER positive breast cancer, we investigated whether a link between the ER, FGFs, and stem cell markers exists in NSCLC. In lung preneoplasias and adenomas of tobacco carcinogen exposed mice, the anti-estrogen fulvestrant and/or the aromatase inhibitor anastrozole blocked FGF2 and FGF9 secretion, and reduced expression of the stem cell markers SOX2 and nanog...
April 11, 2017: Oncotarget
https://www.readbyqxmd.com/read/28424409/clinical-genomic-profiling-to-identify-actionable-alterations-for-investigational-therapies-in-patients-with-diverse-sarcomas
#5
Roman Groisberg, David S Hong, Vijaykumar Holla, Filip Janku, Sarina Piha-Paul, Vinod Ravi, Robert Benjamin, Shreyas Kumar Patel, Neeta Somaiah, Anthony Conley, Siraj M Ali, Alexa B Schrock, Jeffrey S Ross, Philip J Stephens, Vincent A Miller, Shiraj Sen, Cynthia Herzog, Funda Meric-Bernstam, Vivek Subbiah
BACKGROUND: There are currently no United States Food and Drug Administration approved molecularly matched therapies for sarcomas except gastrointestinal stromal tumors. Complicating this is the extreme diversity, heterogeneity, and rarity of these neoplasms. Few therapeutic options exist for relapsed and refractory sarcomas. In clinical practice many oncologists refer patients for genomic profiling hoping for guidance on treatment options after standard therapy. However, a systematic analysis of actionable mutations has yet to be completed...
June 13, 2017: Oncotarget
https://www.readbyqxmd.com/read/28077787/androgen-suppresses-protein-kinase-d1-expression-through-fibroblast-growth-factor-receptor-substrate-2-in-prostate-cancer-cells
#6
Liyong Zhang, Zhenlong Zhao, Shuping Xu, Manuj Tandon, Courtney R LaValle, Fan Deng, Q Jane Wang
In prostate cancer, androgen/androgen receptor (AR) and their downstream targets play key roles in all stages of disease progression. The protein kinase D (PKD) family, particularly PKD1, has been implicated in prostate cancer biology. Here, we examined the cross-regulation of PKD1 by androgen signaling in prostate cancer cells. Our data showed that the transcription of PKD1 was repressed by androgen in androgen-sensitive prostate cancer cells. Steroid depletion caused up regulation of PKD1 transcript and protein, an effect that was reversed by the AR agonist R1881 in a time- and concentration-dependent manner, thus identifying PKD1 as a novel androgen-repressed gene...
February 21, 2017: Oncotarget
https://www.readbyqxmd.com/read/27811184/coupling-an-eml4-alk-centric-interactome-with-rna-interference-identifies-sensitizers-to-alk-inhibitors
#7
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
#8
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 ninth 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 3,167 worldwide approved small-molecule drugs using a repositioning strategy...
April 2017: Chemical Biology & Drug Design
https://www.readbyqxmd.com/read/27615514/proximity-labeling-reveals-molecular-determinants-of-fgfr4-endosomal-transport
#9
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
#10
Oona Delpuech, Claire Rooney, Lorraine Mooney, Dawn Baker, Robert Shaw, Michael Dymond, Dennis Wang, Pei Zhang, Sarah Cross, Margaret Veldman-Jones, Joanne Wilson, Barry R Davies, Jonathan R Dry, Elaine Kilgour, Paul D Smith
The challenge of developing effective pharmacodynamic biomarkers for preclinical and clinical testing of FGFR signaling 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 signaling inhibition by AZD4547, a potent inhibitor of FGF receptors 1, 2, and 3, a gene expression profiling study was performed in FGFR2-amplified, drug-sensitive tumor cell lines...
November 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
#11
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...
September 20, 2016: Oncotarget
https://www.readbyqxmd.com/read/27503856/unravelling-the-mechanism-of-trka-induced-cell-death-by-macropinocytosis-in-medulloblastoma-daoy-cells
#12
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
#13
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...
August 23, 2016: Oncotarget
https://www.readbyqxmd.com/read/27392325/key-roles-of-emt-for-adaptive-resistance-to-mek-inhibitor-in-kras-mutant-lung-cancer
#14
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
#15
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
#16
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 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
#17
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
#18
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
#19
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
#20
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
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