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https://www.readbyqxmd.com/read/28108151/a-functional-genetic-screen-identifies-the-phosphoinositide-3-kinase-pathway-as-a-determinant-of-resistance-to-fibroblast-growth-factor-receptor-inhibitors-in-fgfr-mutant-urothelial-cell-carcinoma
#1
Liqin Wang, Tonći Šuštić, Rodrigo Leite de Oliveira, Cor Lieftink, Pasi Halonen, Marieke van de Ven, Roderick L Beijersbergen, Michel M van den Heuvel, René Bernards, Michiel S van der Heijden
Activating mutations and translocations of the FGFR3 gene are commonly seen in urothelial cell carcinoma (UCC) of the bladder and urinary tract. Several fibroblast growth factor receptor (FGFR) inhibitors are currently in clinical development and response rates appear promising for advanced UCC. A common problem with targeted therapeutics is intrinsic or acquired resistance of the cancer cells. To find potential drug targets that can act synergistically with FGFR inhibition, we performed a synthetic lethality screen for the FGFR inhibitor AZD4547 using a short hairpin RNA library targeting the human kinome in the UCC cell line RT112 (FGFR3-TACC3 translocation)...
January 17, 2017: European Urology
https://www.readbyqxmd.com/read/28107390/melanoma-cell-adhesion-and-migration-is-modulated-by-the-uronyl-2-o-sulfotransferase
#2
Katerina Nikolovska, Dorothe Spillmann, Jörg Haier, Andrea Ladányi, Christian Stock, Daniela G Seidler
Although the vast majority of melanomas are characterized by a high metastatic potential, if detected early, melanoma can have a good prognostic outcome. However, once metastasised, the prognosis is bleak. We showed previously that uronyl-2-O sulfotransferase (Ust) and 2-O sulfation of chondroitin/dermatan sulfate (CS/DS) are involved in cell migration. To demonstrate an impact of 2-O sulfation in metastasis we knocked-down Ust in mouse melanoma cells. This significantly reduced the amount of Ust protein and enzyme activity...
2017: PloS One
https://www.readbyqxmd.com/read/28094372/theoretical-studies-on-fgfr-isoform-selectivity-of-fgfr1-fgfr4-inhibitors-by-molecular-dynamics-simulations-and-free-energy-calculations
#3
Weitao Fu, Lingfeng Chen, Zhe Wang, Yanting Kang, Chao Wu, Qinqin Xia, Zhiguo Liu, Jianmin Zhou, Guang Liang, Yuepiao Cai
The activation and overexpression of fibroblast growth factor receptors (FGFRs) are highly correlated with a variety of cancers. Most small molecule inhibitors of FGFRs selectively target FGFR1-3, but not FGFR4. Hence, designing highly selective inhibitors towards FGFR4 remains a great challenge because FGFR4 and FGFR1 have a high sequence identity. Recently, two small molecule inhibitors of FGFRs, ponatinib and AZD4547, have attracted huge attention. Ponatinib, a type II inhibitor, has high affinity towards FGFR1/4 isoforms, but AZD4547, a type I inhibitor of FGFR1, displays much reduced inhibition toward FGFR4...
January 17, 2017: Physical Chemistry Chemical Physics: PCCP
https://www.readbyqxmd.com/read/28092370/api5-confers-cancer-stem-cell-like-properties-through-the-fgf2-nanog-axis
#4
K-H Song, H Cho, S Kim, H-J Lee, S J Oh, S R Woo, S-O Hong, H S Jang, K H Noh, C H Choi, J-Y Chung, S M Hewitt, J-H Kim, M Son, S-H Kim, B I Lee, H-C Park, Y-K Bae, T W Kim
Immune selection drives the evolution of tumor cells toward an immune-resistant and cancer stem cell (CSC)-like phenotype. We reported that apoptosis inhibitor-5 (API5) acts as an immune escape factor, which has a significant role in controlling immune resistance to antigen-specific T cells, but its functional association with CSC-like properties remains largely unknown. In this study, we demonstrated for the first time that API5 confers CSC-like properties, including NANOG expression, the frequency of CD44-positive cells and sphere-forming capacity...
January 16, 2017: Oncogenesis
https://www.readbyqxmd.com/read/28070720/safety-tolerability-and-pharmacokinetics-of-the-fibroblast-growth-factor-receptor-inhibitor-azd4547-in-japanese-patients-with-advanced-solid-tumours-a-phase-i-study
#5
Hideo Saka, Chiyoe Kitagawa, Yoshihito Kogure, Yasuo Takahashi, Koshi Fujikawa, Tamotsu Sagawa, Satoru Iwasa, Naoki Takahashi, Taro Fukao, Catherine Tchinou, Dónal Landers, Yasuhide Yamada
Background AZD4547 is a potent, oral, highly selective fibroblast growth factor receptor (FGFR) inhibitor in clinical development for treating tumours with a range of FGFR aberrations, including FGFR mutations, amplifications and fusions. Methods This open-label, Phase I, multicentre study (NCT01213160) evaluated the safety, pharmacokinetics, and preliminary antitumour efficacy (RECIST v1.1) of AZD4547 monotherapy in Japanese patients with advanced solid tumours. Part A was a dose-escalation part; Part B was a dose-expansion part in patients with FGFR-amplified tumours, confirmed by fluorescence in situ hybridization...
January 10, 2017: Investigational New Drugs
https://www.readbyqxmd.com/read/28060197/identical-twins-discordant-for-metopic-craniosynostosis-evidence-of-epigenetic-influences
#6
Suresh N Magge, Kendall Snyder, Aparna Sajja, Tiffani A DeFreitas, Sean E Hofherr, Richard E Broth, Robert F Keating, Gary F Rogers
Craniosynostosis, or premature fusion of the cranial sutures, occurs in approximately 1 in 2500 live births. The genetic causes and molecular basis of these disorders have greatly expanded over the last 2 decades, with numerous causative and contributory mutations having been identified. The role of fibroblast growth factor receptor (FGFR) mutations in the etiology of certain eponymous forms of craniosynostosis is now well elucidated; the most common syndromes associated with craniosynostosis are Pfeifer (FGFR1, FGFR2), Apert (FGFR2), Crouzon (FGFR2), Saethre-Chotzen (TWIST1), Jackson-Weiss (FGFR2), Greig (GL13), and Muenke (FGFR3) syndromes...
January 2017: Journal of Craniofacial Surgery
https://www.readbyqxmd.com/read/28056982/different-clinical-significance-of-fgfr1-4-expression-between-diffuse-type-and-intestinal-type-gastric-cancer
#7
Mikito Inokuchi, Hideaki Murase, Sho Otsuki, Tatsuyuki Kawano, Kazuyuki Kojima
BACKGROUND: Receptor tyrosine kinases promote tumor progression in many cancers, although oncologic activation differs between diffuse-type gastric cancer (DGC) and intestinal-type gastric cancer (IGC). Fibroblast growth factor receptor (FGFR) is one RTK, and we previously reported the clinical significance of FGFR1, 2, 3, and 4 in gastric cancer. The aim of the present study was to reevaluate the clinical significance of FGFR1-4 expression separately in DGC and IGC. METHODS: Tumor samples, including 109 DGCs and 100 IGCs, were obtained from patients who underwent gastrectomy between 2003 and 2007 in our institution...
January 5, 2017: World Journal of Surgical Oncology
https://www.readbyqxmd.com/read/28045057/conformational-transition-of-fgfr-kinase-activation-revealed-by-site-specific-unnatural-amino-acid-reporter-and-single-molecule-fret
#8
Louis Perdios, Alan R Lowe, Giorgio Saladino, Tom D Bunney, Nethaji Thiyagarajan, Yuriy Alexandrov, Christopher Dunsby, Paul M W French, Jason W Chin, Francesco Luigi Gervasio, Edward W Tate, Matilda Katan
Protein kinases share significant structural similarity; however, structural features alone are insufficient to explain their diverse functions. Thus, bridging the gap between static structure and function requires a more detailed understanding of their dynamic properties. For example, kinase activation may occur via a switch-like mechanism or by shifting a dynamic equilibrium between inactive and active states. Here, we utilize a combination of FRET and molecular dynamics (MD) simulations to probe the activation mechanism of the kinase domain of Fibroblast Growth Factor Receptor (FGFR)...
January 3, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28041631/targeting-fibroblast-growth-factor-pathways-in-endometrial-cancer
#9
Boris Winterhoff, Gottfried E Konecny
Novel treatments that improve outcomes for patients with recurrent or metastatic endometrial cancer (EC) remain an unmet need. Aberrant signaling by fibroblast growth factors (FGFs) and FGF receptors (FGFRs) has been implicated in several human cancers. Activating mutations in FGFR2 have been found in up to 16% of ECs, suggesting an opportunity for targeted therapy. This review summarizes the role of the FGF pathway in angiogenesis and EC, and provides an overview of FGFR-targeted therapies under clinical development for the treatment of EC...
November 11, 2016: Current Problems in Cancer
https://www.readbyqxmd.com/read/28034880/polyclonal-secondary-fgfr2-mutations-drive-acquired-resistance-to-fgfr-inhibition-in-patients-with-fgfr2-fusion-positive-cholangiocarcinoma
#10
Lipika Goyal, Supriya K Saha, Leah Y Liu, Giulia Siravegna, Ignaty Leshchiner, Leanne G Ahronian, Jochen K Lennerz, Phuong Vu, Vikram Deshpande, Avinash Kambadakone, Benedetta Mussolin, Stephanie Reyes, Laura Henderson, Jiaoyuan Elisabeth Sun, Emily E Van Seventer, Joseph M Gurski, Sabrina Baltschukat, Barbara Schacher-Engstler, Louise Barys, Christelle Stamm, Pascal Furet, David P Ryan, James R Stone, A John Iafrate, Gad Getz, Diana Graus Porta, Ralph Tiedt, Alberto Bardelli, Dejan Juric, Ryan B Corcoran, Nabeel Bardeesy, Andrew X Zhu
Genetic alterations in the fibroblast growth factor receptor (FGFR) pathway are promising therapeutic targets in many cancers, including intrahepatic cholangiocarcinoma (ICC). The FGFR inhibitor BGJ398 displayed encouraging efficacy in patients with FGFR2 fusion-positive ICC in a phase II trial, but the durability of response was limited in some patients. Here, we report the molecular basis for acquired resistance to BGJ398 in three patients via integrative genomic characterization of cell-free circulating tumor DNA (cfDNA), primary tumors, and metastases...
December 29, 2016: Cancer Discovery
https://www.readbyqxmd.com/read/28031461/heparan-sulfate-domains-required-for-fibroblast-growth-factor-1-and-2-signaling-through-fibroblast-growth-factor-receptor-1c
#11
Victor Schultz, Mathew Suflita, Xinyue Liu, Xing Zhang, Yanlei Yu, Lingyun Li, Dixy E Green, Yongmei Xu, Fuming Zhang, Paul L DeAngelis, Jian Liu, Robert J Linhardt
A small library, of well-defined heparan sulfate (HS) polysaccharides, was chemoenzymatically synthesized and used for a detailed structure-activity study of fibroblast growth factor (FGF)1 and FGF2 signaling through FGF receptor (FGFR)1c. The HS polysaccharide tested contained both undersulfated (NA) domains and highly sulfated (NS) domains as well as very well defined non-reducing termini. This study examines differences in the HS selectivity of the positive canyons of the FGF12-FGFR1c2 and FGF22-FGFR1c2 HS-binding sites of the symmetric FGF2-FGFR2HS2 signal transduction complex...
December 28, 2016: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28030802/inhibition-of-the-fibroblast-growth-factor-receptor-fgfr-pathway-the-current-landscape-and-barriers-to-clinical-application
#12
REVIEW
Young Kwang Chae, Keerthi Ranganath, Peter S Hammerman, Christos Vaklavas, Nisha Mohindra, Aparna Kalyan, Maria Matsangou, Ricardo Costa, Benedito Carneiro, Victoria M Villaflor, Massimo Cristofanilli, Francis J Giles
The fibroblast growth factor/fibroblast growth factor receptor (FGF/FGFR) is a tyrosine kinase signaling pathway that has a fundamental role in many biologic processes including embryonic development, tissue regeneration, and angiogenesis. Increasing evidence indicates that this pathway plays a critical role in oncogenesis via gene amplification, activating mutations, or translocation in tumors of various histologies. With multiplex sequencing technology, the detection of FGFR aberrations has become more common and is tied to cancer cell proliferation, resistance to anticancer therapies, and neoangiogenesis...
December 22, 2016: Oncotarget
https://www.readbyqxmd.com/read/28026804/-role-of-fibroblast-growth-factors-in-pancreatic-cancer
#13
REVIEW
D A Gnatenko, E P Kopantsev, E D Sverdlov
Fibroblast growth factors belong to a family of growth factors that are involved in various processes in organism and have a wide range of biological functions. Specifically for pancreas, FGFs are important during both organogenesis and carcinogenesis. One of the main characteristic of pancreatic cancer, is it close interaction between cancer and stromal cells via different factors, including FGF. Pathological changes in FGF/FGFR signaling pathway is a complex process. The remodeling effects and stimulation of tumor growth are mostly depend not only on types of receptors, but also from their isoforms...
November 2016: Biomedit︠s︡inskai︠a︡ Khimii︠a︡
https://www.readbyqxmd.com/read/28019653/mactosylceramide-prevents-glial-cell-overgrowth-by-inhibiting-insulin-and-fibroblast-growth-factor-receptor-signaling
#14
Stine Gerdøe-Kristensen, Viktor K Lund, Hans H Wandall, Ole Kjaerulff
Receptor Tyrosine Kinase (RTK) signaling controls key aspects of cellular differentiation, proliferation, survival, metabolism, and migration. Deregulated RTK signaling also underlies many cancers. Glycosphingolipids (GSL) are essential elements of the plasma membrane. By affecting clustering and activity of membrane receptors, GSL modulate signal transduction, including that mediated by the RTK. GSL are abundant in the nervous system, and glial development in Drosophila is emerging as a useful model for studying how GSL modulate RTK signaling...
December 26, 2016: Journal of Cellular Physiology
https://www.readbyqxmd.com/read/28011645/in-vitro-and-in-vivo-analyses-reveal-profound-effects-of-fibroblast-growth-factor-16-as-a-metabolic-regulator
#15
Ingrid C Rulifson, Patrick Collins, Li Miao, Dana Nojima, Ki Jeong Lee, Miki Hardy, Jamila Gupte, Kelly Hensley, Kim Samayoa, Cynthia Cam, James B Rottman, Mike Ollmann, William G Richards, Yang Li
The discovery of brown adipose tissue (BAT) as a key regulator of energy expenditure has sparked interest in identifying novel soluble factors capable of activating inducible BAT (iBAT) to combat obesity. Using a high content cell-based screen, we identified Fibroblast Growth Factor (FGF) 16 as a potent inducer of several physical and transcriptional characteristics analogous to those of both classical BAT and iBAT. Over-expression of Fgf16 in vivo recapitulated several of our in vitro findings, specifically significant induction of Ucp1 gene and UCP1 protein expression in inguinal white adipose tissue (iWAT), a common site for emergent active iBAT...
December 23, 2016: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28008155/combination-treatment-of-prostate-cancer-with-fgf-receptor-and-akt-kinase-inhibitors
#16
Shu Feng, Longjiang Shao, Patricia Castro, Ilsa Coleman, Peter S Nelson, Paul D Smith, Barry R Davies, Michael Ittmann
Activation of the PI3K/AKT pathway occurs in the vast majority of advanced prostate cancers (PCas). Activation of fibroblast growth factor receptor (FGFR) signaling occurs in a wide variety of malignancies, including PCa. RNA-Seq of castration resistant PCa revealed expression of multiple FGFR signaling components compatible with FGFR signaling in all cases, with multiple FGF ligands expressed in 90% of cases. Immunohistochemistry confirmed FGFR signaling in the majority of xenografts and advanced PCas. AZD5363, an AKT kinase inhibitor and AZD4547, a FGFR kinase inhibitor are under active clinical development...
December 20, 2016: Oncotarget
https://www.readbyqxmd.com/read/27998968/drug-sensitive-fgfr3-mutations-in-lung-adenocarcinoma
#17
P Chandrani, K Prabhash, A Choughule, R Prasad, V Sethunath, M Ranjan, P Iyer, J Aich, H Dhamne, D N Iyer, P Upadhyay, B Mohanty, P Chandna, R Kumar, A Joshi, V Noronha, V Patil, A Ramaswamy, A Karpe, R Thorat, P Chaudhari, A Ingle, A Dutt
BACKGROUND: Lung cancer is the leading cause of cancer-related deaths across the world. In this study we present therapeutically relevant genetic alterations in lung adenocarcinoma of Indian origin. MATERIALS AND METHODS: Forty-five primary lung adenocarcinoma tumors were sequenced for 676 amplicons using RainDance cancer panel at an average coverage of 1500X (reads per million mapped reads). To validate the findings, 49 mutations across 23 genes were genotyped in an additional set of 363 primary lung adenocarcinoma tumors using mass spectrometry...
December 19, 2016: Annals of Oncology: Official Journal of the European Society for Medical Oncology
https://www.readbyqxmd.com/read/27992319/therapeutics-targeting-fgf-signaling-network-in-human-diseases
#18
REVIEW
Masaru Katoh
Fibroblast growth factor (FGF) signaling through its receptors, FGFR1, FGFR2, FGFR3, or FGFR4, regulates cell fate, angiogenesis, immunity, and metabolism. Dysregulated FGF signaling causes human diseases, such as breast cancer, chondrodysplasia, gastric cancer, lung cancer, and X-linked hypophosphatemic rickets. Recombinant FGFs are pro-FGF signaling therapeutics for tissue and/or wound repair, whereas FGF analogs and gene therapy are under development for the treatment of cardiovascular disease, diabetes, and osteoarthritis...
December 2016: Trends in Pharmacological Sciences
https://www.readbyqxmd.com/read/27988457/in-vitro-and-in-vivo-activity-of-lucitanib-in-fgfr1-2-amplified-or-mutated-cancer-models
#19
Federica Guffanti, Rosaria Chilà, Ezia Bello, Massimo Zucchetti, Monique Zangarini, Laura Ceriani, Mariella Ferrari, Monica Lupi, Anne Jacquet-Bescond, Mike F Burbridge, Marie-Jeanne Pierrat, Giovanna Damia
The fibroblast growth factor receptor (FGFR) pathway has been implicated both as an escape mechanism from anti-angiogenic therapy and as a driver oncogene in different tumor types. Lucitanib is a small molecule inhibitor of vascular endothelial growth factor (VEGF) receptors 1 to 3 (VEGFR1 to 3), platelet derived growth factor α/β (PDGFRα/β) and FGFR1-3 tyrosine kinases and has demonstrated activity in a phase I/II clinical study, with objective RECIST responses in breast cancer patients with FGFR1 or FGF3/4/19 gene amplification, as well as in patients anticipated to benefit from anti-angiogenic agents...
December 15, 2016: Neoplasia: An International Journal for Oncology Research
https://www.readbyqxmd.com/read/27988109/receptor-tyrosine-kinases-translocation-partners-in-hematopoietic-disorders
#20
REVIEW
Katelyn N Nelson, Malalage N Peiris, April N Meyer, Asma Siari, Daniel J Donoghue
Receptor tyrosine kinases (RTKs) activate various signaling pathways and regulate cellular proliferation, survival, migration, and angiogenesis. Malignant neoplasms often circumvent or subjugate these pathways by promoting RTK overactivation through mutation or chromosomal translocation. RTK translocations create a fusion protein containing a dimerizing partner fused to an RTK kinase domain, resulting in constitutive kinase domain activation, altered RTK cellular localization, upregulation of downstream signaling, and novel pathway activation...
January 2017: Trends in Molecular Medicine
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