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Y Jiang, H Y Chao, X W Zhang, M Zhou, X Z Lu, R Zhang, C He, Q Wang
Objective: To explore the effects and possible mechanisms of the novel pan-FGFR inhibitor BGJ398 on KG-1 cells in vitro. Methods: Effects of BGJ398 on cells proliferation were detected by CCK-8, the apoptosis was assessed by Annexin V-FITC. Reverse transcriptionquantitative polymerase chain reaction (q-PCR) analysis was used to detect the expression of apoptosis-related genes B cell lymphoma-2 (Bcl-2) and caspase-3. Western blotting analysis was performed to explore the proteins expression levels of Bcl-2, caspase-3 and the expression of p-AKT, p-S6K, p-ERK and FGFR1...
February 14, 2018: Zhonghua Xue Ye Xue za Zhi, Zhonghua Xueyexue Zazhi
Sing-Han Huang, Yu-Shu Lo, Yong-Chun Luo, Yu-Yao Tseng, Jinn-Moon Yang
BACKGROUND: One of the crucial steps toward understanding the associations among molecular interactions, pathways, and diseases in a cell is to investigate detailed atomic protein-protein interactions (PPIs) in the structural interactome. Despite the availability of large-scale methods for analyzing PPI networks, these methods often focused on PPI networks using genome-scale data and/or known experimental PPIs. However, these methods are unable to provide structurally resolved interaction residues and their conservations in PPI networks...
March 19, 2018: BMC Systems Biology
Francesca Andriani, Maria Teresa Majorini, Miguel Mano, Elena Landoni, Rosalba Miceli, Federica Facchinetti, Mavis Mensah, Enrico Fontanella, Matteo Dugo, Mauro Giacca, Ugo Pastorino, Gabriella Sozzi, Domenico Delia, Luca Roz, Daniele Lecis
BACKGROUND: Fibroblasts are crucial mediators of tumor-stroma cross-talk through synthesis and remodeling of the extracellular matrix and production of multiple soluble factors. Nonetheless, little is still known about specific determinants of fibroblast pro-tumorigenic activity in lung cancer. Here, we aimed at understanding the role of miRNAs, which are often altered in stromal cells, in reprogramming fibroblasts towards a tumor-supporting phenotype. METHODS: We employed a co-culture-based high-throughput screening to identify specific miRNAs modulating the pro-tumorigenic potential of lung fibroblasts...
March 20, 2018: Journal of Hematology & Oncology
Stephan Bartels, Akinyele Adisa, Timothy Aladelusi, Juliana Lemound, Angelika Stucki-Koch, Sami Hussein, Hans Kreipe, Christian Hartmann, Ulrich Lehmann, Kais Hussein
The aim of this study was to evaluate the mutation profile of BRAF wild-type craniopharyngiomas and ameloblastomas. Pre-screening by immunohistochemistry and pyrosequencing for identifying BRAF wild-type tumors was performed on archived specimens of ameloblastic tumors (n = 20) and craniopharyngiomas (n = 62). Subsequently, 19 BRAF wild-type tumors (nine ameloblastic tumors and ten craniopharyngiomas) were analyzed further using next-generation sequencing (NGS) targeting hot spot mutations of 22 cancer-related genes...
March 15, 2018: Virchows Archiv: An International Journal of Pathology
Onoufrios Tsavaris, Panagiota Economopoulou, Ioannis Kotsantis, Lazaros Reppas, Chrysanthi Avgerinou, Nikolaos Spathas, Maria Prevezanou, Amanda Psyrri
Chondrosarcoma is a rare malignancy characterized by the production of cartilage matrix, displaying heterogeneous histopathology and clinical behavior. Due to lack of effective treatment for advanced disease, the clinical management of metastatic chondrosarcoma is exceptionally challenging. Chondrosarcomas harbor molecular abnormalities, such as overexpression of platelet-derived growth factor receptor (PDGFR)-alpha and PDGFR-beta, which are required for cancer development, progression, and metastasis. Pazopanib is a potent and selective multitargeted tyrosine kinase inhibitor, which co-inhibits stem cell growth factor receptor (c-KIT), fibroblast growth factor receptor (FGFR), PDGFR, and vascular endothelial growth factor receptor (VEGFR) and has demonstrated clinical activity in patients with advanced previously treated soft tissue sarcoma...
2018: Frontiers in Oncology
Qianjin Li, Omar Awad Alsaidan, Yongjie Ma, Sungjin Kim, Junchen Liu, Thomas Albers, Kebin Liu, Zanna Beharry, Shaying Zhao, Fen Wang, Iryna Lebedyeva, Houjian Cai
Fibroblast growth factor (FGF)/FGF receptor (FGFR) signaling facilitates tumor initiation and progression. Although currently approved inhibitors of FGFR kinase have shown therapeutic benefit in clinical trials, over-expression or mutations of FGFRs eventually confer drug resistance and thereby abrogate the desired activity of kinase inhibitors in many cancer types. In this study, we report that loss of myristoylation of fibroblast growth factor receptor substrate 2 (FRS2α), a scaffold protein essential for FGFR signaling, inhibits FGF/FGFR-mediated oncogenic signaling and FGF10-induced tumorigenesis...
March 14, 2018: Journal of Biological Chemistry
Kumar Parijat Tripathi, Marina Piccirillo, Mario Rosario Guarracino
BACKGROUND: The endomembrane system, known as secretory pathway, is responsible for the synthesis and transport of protein molecules in cells. Therefore, genes involved in the secretory pathway are essential for the cellular development and function. Recent scientific investigations show that ER and Golgi apparatus may provide a convenient drug target for cancer therapy. On the other hand, it is known that abundantly expressed genes in different cellular organelles share interconnected pathways and co-regulate each other activities...
March 8, 2018: BMC Bioinformatics
Ming Dong, Tong Li, Jun Chen
Squamous cell lung cancer (SqCLC) is a unique clinical and histologic category of non-small cell lung cancer (NSCLC). Most of patients with SqCLC tend to be older, typically at advanced stage, associated with smoking and have more complications. With progress of targeted therapy of lung cancer, we identified several potential actionable genetic abnormalities such as FGFR. Several FGFR inhibitors have been approved for clinical use in different cancers. And some of these agents are currently under investigation in clinical trials for SqCLC...
February 20, 2018: Zhongguo Fei Ai za Zhi, Chinese Journal of Lung Cancer
Andrea Necchi, Salvatore Lo Vullo, Daniele Raggi, Annunziata Gloghini, Patrizia Giannatempo, Maurizio Colecchia, Luigi Mariani
FGFR gene alterations represent a target for treatment in clinical trials of urothelial carcinoma (UC). Little is known about their prognostic effect in patients with metastatic UC. We analyzed data for 112 patients treated with platinum-based first-line chemotherapy at our center between October 2011 and March 2017 and who were screened for the presence of FGFR mutations or gene fusions within multiple clinical trials with pan-FGFR inhibitors. Centralized targeted exome sequencing analyses were performed to detect multiple FGFR mutations and fusions...
March 7, 2018: European Urology Focus
Yuming Wang, Lijun Li, Jun Fan, Yang Dai, Alan Jiang, Mei-Yu Geng, Jing Ai, Wenhu Duan
Fibroblast growth factor receptors (FGFR1-4) are promising therapeutic targets in many cancers. With the resurgence of interest in irreversible inhibitors, efforts have been directed to the discovery of irreversible FGFR inhibitors. Currently, several selective irreversible inhibitors are being evaluated in clinical trials that could covalently target a conserved cysteine in the P-loop of FGFR. In this article, we used a structure-guided approach that is rationalized by a computer-aided simulation to discover the novel and irreversible pan-FGFR inhibitor, 9g, which provided superior FGFR in vitro activities and decent selectivity over VEGFR2 (vascular endothelia growth factor receptor 2)...
March 9, 2018: Journal of Medicinal Chemistry
Yuan-Yuan Liu, Min-Bin Chen, Long Cheng, Zhi-Qing Zhang, Zheng-Quan Yu, Qin Jiang, Gang Chen, Cong Cao
We previously identified a pivotal role for G protein α inhibitory subunit 1 (Gαi1) in mediating PI3K-Akt signaling by receptor tyrosine kinases (RTKs). Here, we examined the expression and biological function of Gαi1 in human glioma. Gαi1 mRNA and protein expression were significantly upregulated in human glioma tissues, which correlated with downregulation of an anti-Gαi1 miRNA: microRNA-200a ("miR-200a"). Forced-expression of miR-200a in established (A172/U251MG lines) and primary (patient-derived) human glioma cells resulted in Gαi1 downregulation, Akt inactivation and proliferation inhibition...
March 9, 2018: Oncogene
Hong Luo, Jin Quan, He Xiao, Jia Luo, Qin Zhang, Guocheng Pi, Yunfei Ye, Rong He, Yun Liu, Xiaona Su, Lianhua Zhao, Ge Wang
Activation of fibroblast growth factor receptor (FGFR) signaling occurs in various cancers, including esophageal squamous cell carcinoma (ESCC), however, the effect of targeting FGFR in ESCC is not clear. Herein, we examined the phosphorylation level of FGFR1Y654 (p‑FGFR1) in ESCC cell lines and tumor tissues, as well as the cancer cell killing effects of gefitinib and FGFR inhibitor AZD4547 in combination form or alone in ESCC cells. Immunohistochemistry staining was used to detect the expression level of p‑FGFR1 in 87 ESCC specimens...
March 8, 2018: Oncology Reports
Heglayne Pereira Vital da Silva, Gustavo Henrique de Medeiros Oliveira, Marcela Abbott Galvão Ururahy, João Felipe Bezerra, Karla Simone Costa de Souza, Raul Hernandes Bortolin, André Ducati Luchessi, Vivian Nogueira Silbiger, Valéria Morgiana Gualberto Duarte Moreira Lima, Gisele Correia Pacheco Leite, Maria Edinilma Felinto Brito, Erlane Marques Ribeiro, Vera Lúcia Gil-da-Silva-Lopes, Adriana Augusto de Rezende
BACKGROUND: Although more than 14 loci may be involved in the development of nonsyndromic cleft lip and palate (NSCLP), the etiology has not been fully elucidated due to genetic and environmental risk factor interactions. Despite advances in identifying genes associated with the NSCLP development using traditional genetic mapping strategies of candidate genes, genome-wide studies, and epidemiologic and linkage analysis, microarray techniques have become important complementary tools in the search for potential causative oral clefts genes in genetic studies...
March 7, 2018: Journal of Clinical Laboratory Analysis
Mohamad Moustafa Ali, Vijay Suresh Akhade, Subazini Thankaswamy Kosalai, Santhilal Subhash, Luisa Statello, Matthieu Meryet-Figuiere, Jonas Abrahamsson, Tanmoy Mondal, Chandrasekhar Kanduri
Despite improvement in our understanding of long noncoding RNAs (lncRNAs) role in cancer, efforts to find clinically relevant cancer-associated lncRNAs are still lacking. Here, using nascent RNA capture sequencing, we identify 1145 temporally expressed S-phase-enriched lncRNAs. Among these, 570 lncRNAs show significant differential expression in at least one tumor type across TCGA data sets. Systematic clinical investigation of 14 Pan-Cancer data sets identified 633 independent prognostic markers. Silencing of the top differentially expressed and clinically relevant S-phase-enriched lncRNAs in several cancer models affects crucial cancer cell hallmarks...
February 28, 2018: Nature Communications
Abbie E Fearon, Edward P Carter, Natasha S Clayton, Edmund H Wilkes, Ann-Marie Baker, Ekaterina Kapitonova, Bakhouche A Bakhouche, Yasmine Tanner, Jun Wang, Emanuela Gadaleta, Claude Chelala, Kate M Moore, John F Marshall, Juliette Chupin, Peter Schmid, J Louise Jones, Michelle Lockley, Pedro R Cutillas, Richard P Grose
Development of resistance causes failure of drugs targeting receptor tyrosine kinase (RTK) networks and represents a critical challenge for precision medicine. Here, we show that PHLDA1 downregulation is critical to acquisition and maintenance of drug resistance in RTK-driven cancer. Using fibroblast growth factor receptor (FGFR) inhibition in endometrial cancer cells, we identify an Akt-driven compensatory mechanism underpinned by downregulation of PHLDA1. We demonstrate broad clinical relevance of our findings, showing that PHLDA1 downregulation also occurs in response to RTK-targeted therapy in breast and renal cancer patients, as well as following trastuzumab treatment in HER2+ breast cancer cells...
February 27, 2018: Cell Reports
Sally Yu Shi, Ya-Wen Lu, Zhi Liu, Jennitte Stevens, Christopher M Murawsky, Vicki Wilson, Zhonghua Hu, William G Richards, Mark Leo Michaels, Jun Zhang, Wei Yan, Yang Li
Bispecific antibodies have become important formats for therapeutic discovery. They allow for potential synergy by simultaneously engaging two separate targets and enable new functions that are not possible to achieve by using a combination of two monospecific antibodies. Antagonistic antibodies dominate drug discovery today, but only a limited number of agonistic antibodies (i.e. those that activate receptor signaling) have been described. For receptors formed by two components, engaging both of these components simultaneously may be required for agonistic signaling...
February 26, 2018: Journal of Biological Chemistry
Ai Peng Tan, Wui Khean Chong
BACKGROUND: Apert syndrome is one of the most common craniosynostosis syndrome caused by mutation in genes encoding fibroblast growth factor receptor 2 (FGFR2). Craniosynostosis, midfacial hypoplasia, and syndactyly/symphalangism are features of this syndrome. Sturge-Weber syndrome (SWS) on the other hand is a congenital neurocutaneous disorder characterized by facial port-wine stains (PWSs) and leptomeningeal vascular capillary malformations. In 2013, the causative mutation underlying SWS (p...
February 23, 2018: Child's Nervous System: ChNS: Official Journal of the International Society for Pediatric Neurosurgery
Pasquale Lombardi, Donatella Marino, Elisabetta Fenocchio, Giovanna Chilà, Massimo Aglietta, Francesco Leone
Biliary tract cancers (BTCs) are a heterogeneous group of cancers, characterized by low incidence but poor prognosis. Even after complete surgical resection for early stage, relapse is frequent and the lack of effective treatments contributes to the dismal prognosis. To date, the only standard treatment in first-line is cisplatin/gemcitabine combination, whereas no standard in 2nd -line has been defined. Hence, the current goal is to better understand the biology of BTCs, discovering new treatment methods and improving clinical outcomes...
February 22, 2018: Expert Opinion on Emerging Drugs
Wen Yee Chay, Li Lian Kwok, Wen Ning Tiong, Sai Sakktee Krisna, Kiat Hon Lim, N Gopalkrishna Iyer, Liang Kee Goh, Daniel Shao-Weng Tan
BACKGROUND: Mucinous epithelial ovarian cancers (mEOCs) respond poorly to conventional chemotherapy and have a poor prognosis in advanced stages. The genomic landscape for mEOC in the Asian settings is ill defined. We seek to identify various mutational aberrations present in mEOC and correlate them with clinical outcomes. METHODS: A total of 199 cases of mEOC were identified from a prospectively maintained gynecologic oncology tumor database. DNA was extracted and analyzed for KRAS mutations by using Sanger sequencing...
March 2018: International Journal of Gynecological Cancer
Mélanie Mahe, Florent Dufour, Hélène Neyret-Kahn, Aura Moreno-Vega, Claire Beraud, Mingjun Shi, Imene Hamaidi, Virginia Sanchez-Quiles, Clementine Krucker, Marion Dorland-Galliot, Elodie Chapeaublanc, Remy Nicolle, Hervé Lang, Celio Pouponnot, Thierry Massfelder, François Radvanyi, Isabelle Bernard-Pierrot
FGFR3 alterations (mutations or translocation) are among the most frequent genetic events in bladder carcinoma. They lead to an aberrant activation of FGFR3 signaling, conferring an oncogenic dependence, which we studied here. We discovered a positive feedback loop, in which the activation of p38 and AKT downstream from the altered FGFR3 upregulates MYC mRNA levels and stabilizes MYC protein, respectively, leading to the accumulation of MYC, which directly upregulates FGFR3 expression by binding to active enhancers upstream from FGFR3 Disruption of this FGFR3/MYC loop in bladder cancer cell lines by treatment with FGFR3, p38, AKT, or BET bromodomain inhibitors (JQ1) preventing MYC transcription decreased cell viability in vitro and tumor growth in vivo A relevance of this loop to human bladder tumors was supported by the positive correlation between FGFR3 and MYC levels in tumors bearing FGFR3 mutations, and the decrease in FGFR3 and MYC levels following anti-FGFR treatment in a PDX model bearing an FGFR3 mutation...
February 20, 2018: EMBO Molecular Medicine
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