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https://www.readbyqxmd.com/read/29223420/her2-confers-resistance-to-foretinib-inhibition-of-met-amplified-esophageal-adenocarcinoma-cells
#1
Alexei A Goltsov, Bingliang Fang, Tej K Pandita, Dipen M Maru, Stephen G Swisher, Wayne L Hofstetter
BACKGROUND: Recent genomic studies indicated that esophageal adenocarcinoma (EAC) is driven by amplification of c-MET or HER2 or both in a subset of patients. We studied the effect of MET targeting by the small molecule inhibitor foretinib in EAC cells and the interplay between MET and HER2 signaling. METHODS: We measured the expression levels and phosphorylation status of MET and HER2 proteins in EAC cell lines using Western blot analysis. The expression levels of MET and HER2 were manipulated by transfecting cells with specific siRNA or a plasmid expressing HER2...
December 6, 2017: Annals of Thoracic Surgery
https://www.readbyqxmd.com/read/29219657/the-levels-of-mutant-k-ras-and-mutant-n-ras-are-rapidly-reduced-in-a-beclin1-atg5-dependent-fashion-by-the-irreversible-erbb1-2-4-inhibitor-neratinib
#2
Laurence Booth, Jane L Roberts, Andrew Poklepovic, John Kirkwood, Cindy Sander, Francesca Avogadri-Connors, Richard E Cutler, Alshad S Lalani, Paul Dent
The FDA approved irreversible inhibitor of ERBB1/2/4, neratinib, was recently shown to rapidly down-regulate the expression of ERBB1/2/4 as well as the levels of c-MET and mutant K-RAS via autophagic degradation. In the present studies, in a dose-dependent fashion, neratinib reduced the expression levels of mutant K-RAS or of mutant N-RAS, which was augmented in an additive to greater than additive fashion by the HDAC inhibitors sodium valproate and AR42. Neratinib could reduce PDGFRα levels in GBM cells, that was enhanced by sodium valproate...
December 8, 2017: Cancer Biology & Therapy
https://www.readbyqxmd.com/read/29212158/rnascope-in-situ-hybridization-confirms-mrna-integrity-in-formalin-fixed-paraffin-embedded-cancer-tissue-samples
#3
Victoria Bingham, Leanne McIlreavey, Christine Greene, Edwina O'Doherty, Rebecca Clarke, Stephanie Craig, Manuel Salto-Tellez, Stephen McQuaid, Claire Lewis, Jacqueline James
Immunohistochemistry remains the overwhelming technique of choice for test biomarker evaluation in both clinical or research settings when using formalin-fixed, paraffin embedded tissue sections. However, validations can be complex with significant issues about specificity, sensitivity and reproducibility. The vast array of commercially available antibodies from many vendors may also lead to non-standard approaches which are difficult to cross-reference. In contrast mRNA detection, by in situ hybridization (ISH) with sequence specific probes, offers a realistic alternative, with less validation steps and more stringent and reproducible assessment criteria...
November 7, 2017: Oncotarget
https://www.readbyqxmd.com/read/29206199/a-novel-receptor-tyrosine-kinase-switch-promotes-gastrointestinal-stromal-tumor-drug-resistance
#4
Sergei Boichuk, Aigul Galembikova, Pavel Dunaev, Elena Valeeva, Elena Shagimardanova, Oleg Gusev, Svetlana Khaiboullina
The fact that most gastrointestinal stromal tumors (GISTs) acquire resistance to imatinib (IM)-based targeted therapy remains the main driving force to identify novel molecular targets that are capable to increase GISTs sensitivity to the current therapeutic regimens. Secondary resistance to IM in GISTs typically occurs due to several mechanisms that include hemi- or homo-zygous deletion of the wild-type KIT allele, overexpression of focal adhesion kinase (FAK) and insulin-like growth factor receptor I (IGF-1R) amplification, BRAF mutation, a RTK switch (loss of c-KIT and gain of c-MET/AXL), etc...
December 5, 2017: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
https://www.readbyqxmd.com/read/29203143/synthesis-and-bioevaluation-study-of-novel-n-methylpicolinamide-and-thienopyrimidine-derivatives-as-selectivity-c-met-kinase-inhibitors
#5
Linxiao Wang, Shan Xu, Xiuying Chen, Xiaobo Liu, Yongli Duan, Dejia Kong, Dandan Zhao, Pengwu Zheng, Qidong Tang, Wufu Zhu
Four series of N-methylpicolinamide moiety and thienopyrimidine moiety bearing pyridazinone were designed and synthesized and evaluated for the IC50 values against three cancer cell lines (A549, HepG2 and MCF-7) and some selected compounds were further evaluated for the activity against c-Met, Flt-3, VEGFR-2, c-Kit and EGFR kinases. Three compounds (35, 39 and 43) showed more active than positive control Foretinib against A549, HepG2 and MCF-7 cell lines. The most promising compound 43 showed superior activity against A549, HepG2 and MCF-7, with the IC50 values of 0...
November 26, 2017: Bioorganic & Medicinal Chemistry
https://www.readbyqxmd.com/read/29203124/activation-of-the-hgf-c-met-axis-in-the-tumor-microenvironment-a-multispecies-model
#6
Anna Konstorum, John S Lowengrub
The tumor microenvironment is an integral component in promoting tumor development. Cancer-associated fibroblasts (CAFs), which reside in the tumor stroma, produce Hepatocyte Growth Factor (HGF), an important trigger for invasive and metastatic tumor behavior. HGF contributes to a pro-tumorigenic environment by activating its cognate receptor, c-Met, on tumor cells. Tumor cells, in turn, secrete growth factors that upregulate HGF production in CAFs, thereby establishing a dynamic tumor-host signaling program...
December 1, 2017: Journal of Theoretical Biology
https://www.readbyqxmd.com/read/29202410/discovery-optimization-and-biological-evaluation-for-novel-c-met-kinase-inhibitors
#7
Haoliang Yuan, Qiufeng Liu, Li Zhang, Shihe Hu, Tiantian Chen, Huifang Li, Yadong Chen, Yechun Xu, Tao Lu
The c-Met kinase has emerged as an attractive target for developing antitumor agents because of its close relationship with the development of many human cancers, poor clinical outcomes and even drug resistance. A series of novel c-Met kinase inhibitors have been identified with multiple workflow in this work, including virtual screening, X-ray crystallography, biological evaluation and structural optimization. The experimentally determined crystal structure of the best hit compound HL-11 in c-Met kinase domain was highly consistent with the computational prediction...
December 1, 2017: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/29200829/andrographolide-enhanced-5-fluorouracil-induced-antitumor-effect-in-colorectal-cancer-via-inhibition-of-c-met-pathway
#8
Meng Su, Baoli Qin, Fang Liu, Yuze Chen, Rui Zhang
Colorectal cancer (CRC) is the third most common malignant neoplasm worldwide. 5-Fluorouracil (5-Fu) is the most important chemotherapeutic drug used for the treatment of CRC. However, resistance to 5-Fu therapies is a growing concern in CRC clinical practice recently. Andrographolide (Andro) is a main bioactive constituent of the herb Andrographis paniculata, which has various biological effects including anti-inflammation and antitumor activities. In the present study, we investigated the effects of combined Andro with 5-Fu against CRC HCT-116 cells...
2017: Drug Design, Development and Therapy
https://www.readbyqxmd.com/read/29199218/uses-of-cyclohexan-1-4-dione-for-the-synthesis-of-2-amino-4-5-dihydrobenzo-b-thiophen-6-7h-one-derivatives-with-anti-proliferative-and-pim-1-kinase-activities
#9
Rafat Milad Mohareb, Nermeen Saeed Abbas, Rehab Ali Ibrahim
The reaction of cyclohexan-1,4-dione with elemental sulfur and any of the 2-cyano-N-arylacetamide derivatives 2a-c gave the 2-amino-4,5-dihydrobenzo[b]thiophen-6(7H)-one derivatives 3a-c to be used in some heterocyclization reactions. The multicomponent reactions of any of compounds 3a-c with aromatic aldehydes 6a-c and either of malononitrile or ethylcyanoacetate gave the 5,9-dihydro-4H-thieno[2,3-f]chromene derivatives 9a-r, respectively. The anti-proliferative evaluation of the newly synthesized compounds against the six cancer cell lines A549, HT-29, MKN-45, U87MG, SMMC-7721 and H460 showed that the nine compounds 3c, 5c, 9e, 9h, 9i, 9j, 9l, 9q, 11e and 13e with highest cytotoxcity...
2017: Chemical & Pharmaceutical Bulletin
https://www.readbyqxmd.com/read/29197731/synthesis-and-antiproliferative-activity-of-pyrrolo-2-3-b-pyridine-derivatives-bearing-the-1-8-naphthyridin-2-one-moiety
#10
Qidong Tang, Yongli Duan, Linxiao Wang, Min Wang, Yiqiang Ouyang, Caolin Wang, Han Mei, Sheng Tang, Yinhua Xiong, Pengwu Zheng, Ping Gong, Wufu Zhu
A series of pyrrolo[2,3-b]pyridine derivatives bearing the 1,8-naphthyridin-2-one moiety were synthesized, and evaluated for their antiproliferative activity against four cancer cell lines (HT-29, A549, H460, and U87MG) and six tyrosine kinases (c-Met, Flt-3, PDGFR-β, VEGFR-2, EGFR, and c-Kit) inhibitory activities in vitro. Most compounds showed moderate to excellent potency, with the most promising analogue 32 showing Flt-3/c-Met IC50 value of 1.16/1.92 nM. Structure-activity relationship studies indicated that the hydrogen atom served as R1 group was benefited to the potency, and mono-electron-withdrawing groups (mono-EWGs) on the phenyl ring (such as R3 = 4-F) showed a higher preference for antiproliferative activity...
November 21, 2017: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/29187584/a-novel-bispecific-c-met-ctla-4-antibody-targeting-lung-cancer-stem-cell-like-cells-with-therapeutic-potential-in-human-non-small-cell-lung-cancer
#11
Jian-Feng Li, Yuan-Yuan Niu, Yan-Li Xing, Feng Liu
A novel paradigm in tumor biology suggests that non-small cell lung cancer (NSCLC) growth is driven by lung cancer stem cell-like cells (LCSCs), but here are still not any effective strategies to remove LCSCs. The bispecific antibody is a novel antibody, which can target two different antigens and mediate specific killing effects by selectively redirecting effector cells to the target cells. Here, we designed and synthesized a new bispecific antibody (BsAb), BsAb-5, that can target cellular-mesenchymal to epithelial transition factor (c-MET) and cytotoxic T-lymphocyte associated protein 4 (CTLA-4) in CD166+ LCSCs with high affinity and specificity, for the first time...
November 29, 2017: Bioscience Reports
https://www.readbyqxmd.com/read/29187145/-sussing-that-doctor-out-experiences-and-perspectives-of-people-affected-by-hepatitis-c-regarding-engagement-with-private-general-practitioners-in-south-australia-a-qualitative-study
#12
Jane Scarborough, Emma Ruth Miller, Paul Aylward, Jaklin Eliott
BACKGROUND: Australians with chronic hepatitis C (HCV) can access affordable Direct Acting Antiviral (DAA) treatments with high cure rates (>90%), via General Practitioners (GPs). Benefits from this treatment will be maximised if people with HCV readily disclose and engage with private GPs regarding HCV-related issues. Investigating the perceptions and experiences of people affected by HCV with GPs can allow for this pathway to care for HCV to be improved. METHODS: In 2013-2014, 22 purposively sampled participants from South Australia (SA) were interviewed...
November 29, 2017: BMC Family Practice
https://www.readbyqxmd.com/read/29176766/establishment-of-an-indirect-elisa-for-detection-of-the-novel-antifibrotic-peptide-m10
#13
Tanjina Akter, Ilia Atanelishvili, Atsushi Noguchi, Richard M Silver, Galina S Bogatkevich
OBJECTIVE: M10 is a ten amino acid peptide generated from the intracellular cytoplasmic tail of the hepatocyte growth factor (HGF) receptor c-Met following cleavage by caspase-3. Recently we reported that M10 interacts with Smad2 and demonstrates antifibrotic properties in vitro and in vivo and can be advanced into a novel antifibrotic remedy. The current study was undertaken to develop an immunoassay to measure M10 concentration in biological specimens. EXPERIMENTAL DESIGN: An Indirect Enzyme-Linked Immunosorbent Assay (ELISA) for detection of M10 in biological fluids was developed using pharmaceutical grade synthetic M10 as a calibrator and commercially available anti-c-Met C12 antibody...
2017: PloS One
https://www.readbyqxmd.com/read/29175587/design-synthesis-and-molecular-modeling-studies-of-new-series-of-antitumor-1-2-4-triazines-with-potential-c-met-kinase-inhibitory-activity
#14
Marwa H El-Wakil, Hayam M Ashour, Manal N Saudi, Ahmed M Hassan, Ibrahim M Labouta
The receptor tyrosine kinase c-Met is an attractive target for therapeutic treatment of cancers nowadays. Herein we describe the design and synthesis of a novel series of 1,2,4-triazine derivatives based on our lead NCI 748494/1, possessing different N-linkers to aromatic and heterocyclic rings. In addition, a molecular hybrid series combining the 1,2,4-triazine scaffold to the well-known anticancer drug 6-mercaptopurine (6-MP) was synthesized in order to explore its "double-drug" antitumor effect. The synthesized compounds were evaluated for their in vitro antitumor activity against three c-Met addicted cancer cell lines (A549, HT-29 and MKN-45)...
November 16, 2017: Bioorganic Chemistry
https://www.readbyqxmd.com/read/29174801/dual-targeting-c-met-and-vegfr2-in-osteoblasts-suppresses-growth-and-osteolysis-of-prostate-cancer-bone-metastasis
#15
Changki Lee, Young Mi Whang, Preston Campbell, Patrick L Mulcrone, Florent Elefteriou, Sun Wook Cho, Serk In Park
Prostate cancer characteristically induces osteoblastic bone metastasis, for which no therapies are available. A dual kinase inhibitor of c-Met and VEGFR-2 (cabozantinib) was shown to reduce prostate cancer growth in bone, with evidence for suppressing osteoblastic activity. However, c-Met and VEGFR2 signaling in osteoblasts in the context of bone metastasis remain unclear. Here we show using cultured osteoblasts that hepatocyte growth factor (HGF) and VEGF-A increased receptor activator of NFκB ligand (RANKL) and M-CSF, two essential factors for osteoclastogenesis...
November 21, 2017: Cancer Letters
https://www.readbyqxmd.com/read/29163834/prognostic-value-of-c-met-overexpression-in-hepatocellular-carcinoma-a-meta-analysis-and-review
#16
Jung Han Kim, Hyeong Su Kim, Bum Jun Kim, Hyun Joo Jang, Jin Lee
The overexpression of c-Met protein has been detected in hepatocellular carcinoma (HCC). However, its prognostic impact remains uncertain. We performed this meta-analysis to evaluate the prognostic value of c-Met overexpression in patients who underwent curative surgical resection for HCC. A systematic computerized search of the electronic databases was carried out. From 5 studies, 1,408 patients who underwent surgical resection for HCC were included in the meta-analysis. Compared with patients with HCC having low c-Met expression, patients with c-Met-high tumor showed significantly worse relapse-free survival (hazard ratio = 1...
October 27, 2017: Oncotarget
https://www.readbyqxmd.com/read/29163826/hdac-inhibitors-enhance-neratinib-activity-and-when-combined-enhance-the-actions-of-an-anti-pd-1-immunomodulatory-antibody-in-vivo
#17
Laurence Booth, Jane L Roberts, Andrew Poklepovic, Francesca Avogadri-Connors, Richard E Cutler, Alshad S Lalani, Paul Dent
Patients whose NSCLC tumors become afatinib resistant presently have few effective therapeutic options to extend their survival. Afatinib resistant NSCLC cells were sensitive to clinically relevant concentrations of the irreversible pan-HER inhibitor neratinib, but not by the first generation ERBB1/2/4 inhibitor lapatinib. In multiple afatinib resistant NSCLC clones, HDAC inhibitors reduced the expression of ERBB1/3/4, but activated c-SRC, which resulted in higher total levels of ERBB1/3 phosphorylation. Neratinib also rapidly reduced the expression of ERBB1/2/3/4, c-MET and of mutant K-/N-RAS; K-RAS co-localized with phosphorylated ATG13 and with cathepsin B in vesicles...
October 27, 2017: Oncotarget
https://www.readbyqxmd.com/read/29163704/riparsaponin-isolated-from-homonoia-riparia-lour-induces-apoptosis-of-oral-cancer-cells
#18
Tiecheng Li, Lei Wang
Homonoia riparia Lour (Euphorbiaceae) is a known source of herbal medicine in China, and riparsaponin (RSP) is an active constituent isolated from H. riparia. The aim of the present study was to investigate the antitumor effect of RSP on human oral carcinoma cells and its potential underlying molecular mechanism. RSP was isolated from roots of H. riparia and identified using nuclear magnetic resonance. An MTT assay was used to evaluate the cytotoxicity of RSP on human oral carcinoma cells. Subsequently, DAPI staining was performed to investigate the apoptotic effect of RSP...
December 2017: Oncology Letters
https://www.readbyqxmd.com/read/29157685/recent-advances-in-the-discovery-of-small-molecule-c-met-kinase-inhibitors
#19
REVIEW
Palak K Parikh, Manjunath D Ghate
c-Met is a prototype member of a subfamily of heterodimeric receptor tyrosine kinases (RTKs) and is the receptor for hepatocyte growth factor (HGF). Binding of HGF to its receptor c-Met, initiates a wide range of cellular signalling, including those involved in proliferation, motility, migration and invasion. Importantly, dysregulated HGF/c-Met signalling is a driving factor for numerous malignancies and promotes tumour growth, invasion, dissemination and/or angiogenesis. Dysregulated HGF/c-Met signalling has also been associated with poor clinical outcomes and resistance acquisition to some approved targeted therapies...
August 24, 2017: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/29156728/long-non-coding-rna-hotair-acts-as-a-competing-endogenous-rna-to-promote-malignant-melanoma-progression-by-sponging-mir-152-3p
#20
Wenkang Luan, Rubo Li, Liang Liu, Xin Ni, Yan Shi, Yun Xia, Jinlong Wang, Feng Lu, Bin Xu
HOX transcript antisense RNA (HOTAIR) is associated with the growth and metastasis of many human tumors, but its biological roles in malignant melanoma remain unclear. In this study, we show that HOTAIR is overexpressed in melanoma tissues and cells, especially in metastatic melanoma. High HOTAIR levels correlate with poor prognosis in melanoma patients. We also determined that HOTAIR functions as a competing endogenous RNA (ceRNA) for miR-152-3p. miR-152-3p was decreased and acted as a tumor suppressor in melanoma, and c-MET was the functional target of miR-152-3p...
October 17, 2017: Oncotarget
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