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https://www.readbyqxmd.com/read/29327716/genomic-heterogeneity-of-alk-fusion-breakpoints-in-non-small-cell-lung-cancer
#1
Jason N Rosenbaum, Ryan Bloom, Jason T Forys, Jeff Hiken, Jon R Armstrong, Julie Branson, Samantha McNulty, Priya D Velu, Kymberlie Pepin, Haley Abel, Catherine E Cottrell, John D Pfeifer, Shashikant Kulkarni, Ramaswamy Govindan, Eric Q Konnick, Christina M Lockwood, Eric J Duncavage
In lung adenocarcinoma, canonical EML4-ALK inversion results in a fusion protein with a constitutively active ALK kinase domain. Evidence of ALK rearrangement occurs in a minority (2-7%) of lung adenocarcinoma, and only ~60% of these patients will respond to targeted ALK inhibition by drugs such as crizotinib and ceritinib. Clinically, targeted anti-ALK therapy is often initiated based on evidence of an ALK genomic rearrangement detected by fluorescence in situ hybridization (FISH) of interphase cells in formalin-fixed, paraffin-embedded tissue sections...
January 12, 2018: Modern Pathology: An Official Journal of the United States and Canadian Academy of Pathology, Inc
https://www.readbyqxmd.com/read/29290262/gcc2-alk-as-a-targetable-fusion-in-lung-adenocarcinoma-and-its-enduring-clinical-responses-to-alk-inhibitors
#2
Junhong Jiang, Xue Wu, Xiaoling Tong, Wangzhi Wei, Anan Chen, Xiaonan Wang, Yang W Shao, Jianan Huang
OBJECTIVES: ALK, RET and ROS1 fusions have been identified as treatable targets in 5%-15% of non-small-cell lung cancers, and thanks to the advanced sequencing technologies, their new partner genes have been steadily detected. Here we identified a rare fusion of ALK (GCC2-ALK) in a patient with advanced lung adenocarcinoma and monitored the treatment efficacy of ALK inhibitors on this patient. We further performed in vitro functional studies of this fusion protein for evaluating its oncogenic potential...
January 2018: Lung Cancer: Journal of the International Association for the Study of Lung Cancer
https://www.readbyqxmd.com/read/29284707/structural-alterations-of-met-trigger-response-to-met-kinase-inhibition-in-lung-adenocarcinoma-patients
#3
Dennis Plenker, Miriam Bertrand, Adrianus Johannes de Langen, Richard Riedel, Carina Lorenz, Andreas H Scheel, Judith Nadja Müller, Johannes Brägelmann, Juliane Daßler-Plenker, Carsten Kobe, Thorsten Persigehl, Alexander Kluge, Thomas Wurdinger, Pepijn Schellen, Gunther Hartmann, Tobias Zacherle, Roopika Menon, Erik Thunnissen, Reinhard Büttner, Frank Griesinger, Juergen Wolf, Lukas Heukamp, Johannes M Heuckmann, Martin L Sos
PURPOSE: We sought to investigate the clinical response to MET inhibition in patients diagnosed with structural MET alterations and to characterize their functional relevance in cellular models. EXPERIMENTAL DESIGN: Patients were selected for treatment with crizotinib upon results of hybrid capture-based next generation sequencing. To confirm the clinical observations we analyzed cellular models that express these MET kinase alterations. RESULTS: Three individual patients were identified to harbor alterations within the MET receptor...
December 28, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/29279550/anaplastic-large-cell-lymphoma-pathology-genetics-and-clinical-aspects
#4
Naoko Tsuyama, Kana Sakamoto, Seiji Sakata, Akito Dobashi, Kengo Takeuchi
Anaplastic large cell lymphoma (ALCL) was first described in 1985 as a large-cell neoplasm with anaplastic morphology immunostained by the Ki-1 antibody, which recognizes CD30. In 1994, the nucleophosmin (NPM)-anaplastic lymphoma kinase (ALK) fusion receptor tyrosine kinase was identified in a subset of patients, leading to subdivision of this disease into ALK-positive and -negative ALCL in the present World Health Organization classification. Due to variations in morphology and immunophenotype, which may sometimes be atypical for lymphoma, many differential diagnoses should be considered, including solid cancers, lymphomas, and reactive processes...
2017: Journal of Clinical and Experimental Hematopathology: JCEH
https://www.readbyqxmd.com/read/29202023/combating-drug-resistant-mutants-of-anaplastic-lymphoma-kinase-with-potent-and-selective-type-i1-2-inhibitors-by-stabilizing-unique-dfg-shifted-loop-conformation
#5
Peichen Pan, Huidong Yu, Qinglan Liu, Xiaotian Kong, Hu Chen, Jiean Chen, Qi Liu, Dan Li, Yu Kang, Huiyong Sun, Wenfang Zhou, Sheng Tian, Sunliang Cui, Feng Zhu, Youyong Li, Yong Huang, Tingjun Hou
Targeted inhibition of anaplastic lymphoma kinase (ALK) dramatically improved therapeutic outcomes in the treatment of ALK-positive cancers, but unfortunately patients invariably progressed due to acquired resistance mutations in ALK. Currently available drugs are all type-I inhibitors bound to the ATP-binding pocket and are most likely to be resistant in patients harboring genetic mutations surrounding the ATP pocket. To overcome drug resistance, we rationally designed a novel kind of "bridge" inhibitor, which specially bind into an extended hydrophobic back pocket adjacent to the ATP-binding site of ALK...
November 22, 2017: ACS Central Science
https://www.readbyqxmd.com/read/29199697/anaplastic-lymphoma-kinase-status-in-lung-cancers-an-immunohistochemistry-and-fluorescence-in-situ-hybridization-study-from-a-tertiary-cancer-center-in-india
#6
S S Murthy, S J Rajappa, S D Gundimeda, K M Mallavarapu, S Ayyagari, P Yalavarthi, D Fonseca, P Paliwal, Hgr Nair, V Koppula, Kvvn Raju, S T Rao
BACKGROUND AND OBJECTIVES: Fluorescence in situ hybridization (FISH) and immunohistochemistry (IHC) have shown good concordance for the detection of echinoderm microtubule-associated protein-like 4 and anaplastic lymphoma kinase (ALK) rearrangement. Since studies reporting FISH/IHC concordance, clinicopathological features, and clinical outcomes of ALK-positive patients from India are lacking, this study was undertaken. MATERIALS AND METHODS: This is a retrospective, observational study of patients with adenocarcinoma of the lung on whom ALK test was performed between March 2013 and December 2015...
January 2017: Indian Journal of Cancer
https://www.readbyqxmd.com/read/29199678/ceritinib-in-anaplastic-lymphoma-kinase-positive-nonsmall-cell-lung-cancer-among-patients-who-were-previously-exposed-to-crizotinib-experience-from-the-indian-subcontinent
#7
A P Joshi, M V Chandrakanth, V Noronha, V Patil, A Chougule, A Mahajan, A K Janu, R Chanana, K Prabhash
Ceritinib is a novel ALK inhibitor approved for advanced stage NSCLC with ALK gene rearrangement, progressed and/or intolerant to crizotinib. 13 patients were included in our study who received ceritinib. Majority of them were women and never smokers with a median age of 47 yrs. Nearly half of them had a compromised performance status and received ceritinib in third line and beyond. Ceritinib showed nearly 50% response rates. With a median follow up of 9 months for the entire cohort, median PFS and OS were not reached...
January 2017: Indian Journal of Cancer
https://www.readbyqxmd.com/read/29187012/targeted-therapies-in-non-small-cell-lung-cancer-a-focus-on-alk-ros1-tyrosine-kinase-inhibitors
#8
Assunta Sgambato, Francesca Casaluce, Paolo Maione, Cesare Gridelli
Anaplastic lymphoma kinase (ALK) and ROS1 rearrangements define important molecular subgroups of advanced non-small cell lung cancer (NSCLC). The identification of these genetic driver alterations created new potential for highly active therapeutic interventions. After discovery of ALK rearrangements in NSCLC, it was recognized that these confer sensitivity to ALK inhibition. Areas covered: Crizotinib, the first-in-class ALK/ROS1/MET inhibitor, was initially approved as second-line treatment of ALK-positive advanced NSCLC but after this, it was firmly established as the standard first-line therapy for advanced ALK-positive NSCLC...
January 2018: Expert Review of Anticancer Therapy
https://www.readbyqxmd.com/read/29180737/polypharmacology-repurposing-ceritinib
#9
Sarah Crunkhorn
No abstract text is available yet for this article.
November 28, 2017: Nature Reviews. Drug Discovery
https://www.readbyqxmd.com/read/29174809/discovery-of-novel-2-4-diarylaminopyrimidine-analogues-as-alk-and-ros1-dual-inhibitors-to-overcome-crizotinib-resistant-mutants-including-g1202r
#10
Yu Wang, Shaowei Chen, Gang Hu, Jiao Wang, Wenfeng Gou, Daiying Zuo, Yucheng Gu, Ping Gong, Xin Zhai
Aiming to explore novel anaplastic lymphoma kinase (ALK) and proto-oncogene tyrosine-protein kinase ROS (ROS1) dual inhibitors to overcome crizotinib-resistant mutants, two series of 2,4-diarylaminopyrimidine (DAAP) analogues bearing thiazole or 1,2,3-triazole moieties were designed and synthesized based upon the cocrystal structure of ceritinib with ALKWT (PDB 4MKC) as well as the binding model of ceritinib with ALKG1202R. The cellular and enzymatic assays validated 34c (WY-135) as a promising ALK (IC50 = 1...
November 6, 2017: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/29174221/lung-toxicity-in-non-small-cell-lung-cancer-patients-exposed-to-alk-inhibitors-report-of-a-peculiar-case-and-systematic-review-of-the-literature
#11
REVIEW
Benedetta Pellegrino, Francesco Facchinetti, Paola Bordi, Mario Silva, Letizia Gnetti, Marcello Tiseo
Lung toxicity is a potential fatal effect involving non-small-cell lung cancer (NSCLC) patients exposed to tyrosine kinase inhibitors (TKIs). Moving from our experience regarding a patient who developed lung toxicity while receiving 2 different anaplastic lymphoma kinase (ALK)-TKIs, we performed a systematic review to assess the epidemiologic magnitude and the clinical significance of such toxicity in NSCLC patients treated with ALK-TKIs. Studies were identified using MEDLINE and additional sources (European Society for Medical Oncology, American Society of Clinical Oncology, and World Conference on Lung Cancer abstracts) in agreement with Preferred Reporting Items for Systematic Reviews and Meta-Analyses and Cochrane guidelines...
October 28, 2017: Clinical Lung Cancer
https://www.readbyqxmd.com/read/29165815/development-and-validation-of-a-liquid-chromatography-tandem-mass-spectrometry-analytical-method-for-the-therapeutic-drug-monitoring-of-eight-novel-anticancer-drugs
#12
M Herbrink, N de Vries, H Rosing, A D R Huitema, B Nuijen, J H M Schellens, J H Beijnen
To support therapeutic drug monitoring (TDM) of patients with cancer, a fast and accurate method for simultaneous quantification of the registered anticancer drugs afatinib, axitinib, ceritinib, crizotinib, dabrafenib, enzalutamide, regorafenib and trametinib in human plasma using liquid chromatography tandem mass spectrometry was developed and validated. Human plasma samples were collected from treated patients and stored at -20 (o) C. Analytes and internal standards (stable isotopically labeled analytes) were extracted with acetonitrile...
November 22, 2017: Biomedical Chromatography: BMC
https://www.readbyqxmd.com/read/29137103/crizotinib-resistance-overcome-by-ceritinib-in-an-alk-positive-non-small-cell-lung-cancer-patient-with-brain-metastases-a-case-report
#13
Zhouyu Zhu, Ying Chai
RATIONALE: The treatment of non-small cell lung cancer (NSCLC) has now changed dramatically in recent years and anaplastic lymphoma receptor tyrosine kinase (ALK) inhibitors are developing rapidly. PATIENT CONCERNS: Here we reported a 57-year-old ALK-positive NSCLC man with brain metastases. DIAGNOSES: A case of lung adenocarcinoma with brain metastases. INTERVENTIONS: Crizotinib was administered orally at a dose of 250mg twice a day until the brain metastases were found...
November 2017: Medicine (Baltimore)
https://www.readbyqxmd.com/read/29135281/ceritinib-compassionate-use-for-patients-with-crizotinib-refractory-anaplastic-lymphoma-kinase-positive-advanced-non-small-cell-lung-cancer
#14
Giulio Metro, Antonio Passaro, Giuseppe Lo Russo, Laura Bonanno, Raffaele Giusti, Vanesa Gregorc, Enrica Capelletto, Olga Martelli, Fabiana L Cecere, Diana Giannarelli, Andrea Luciani, Alessandra Bearz, Alessandro Tuzi, Vieri Scotti, Giuseppe Tonini, Domenico Galetta, Annamaria Carta, Hector Soto Parra, Alberto Rebonato, Alessandro Morabito, Rita Chiari
AIM: Ceritinib was evaluated within a compassionate use program of Italian patients. PATIENTS & METHODS: 70 patients with anaplastic lymphoma kinase-positive crizotinib-refractory advanced non-small-cell lung cancer received ceritinib. RESULTS: Overall response was 40.6%, median progression-free survival was 8.2 months and median survival was 15.5 months. Dose reduction due to treatment-related adverse events occurred in 50.8% of patients starting at 750 mg/day...
November 14, 2017: Future Oncology
https://www.readbyqxmd.com/read/29133622/ceritinib-enhances-the-efficacy-of-trametinib-in-braf-nras-wild-type-melanoma-cell-lines
#15
Daniel Verduzco, Brent M Kuenzi, Fumi Kinose, Vernon K Sondak, Zeynep Eroglu, Uwe Rix, Keiran S M Smalley
Targeted therapy options are currently lacking for the heterogeneous population of patients whose melanomas lack BRAF or NRAS mutations (~35% of cases). We undertook a chemical biology screen to identify potential novel drug targets for this understudied group of tumors. Screening a panel of 8 BRAF/NRAS-WT melanoma cell lines against 240 targeted drugs identified ceritinib and trametinib as potential hits with single agent activity. Ceritinib enhanced the efficacy of trametinib across the majority of the BRAF/NRAS-WT cell lines, and the combination showed increased cytotoxicity in both 3D spheroid culture and long-term colony formation experiments...
November 13, 2017: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/29067644/targeting-anaplastic-lymphoma-kinase-alk-in-rhabdomyosarcoma-rms-with-the-second-generation-alk-inhibitor-ceritinib
#16
Anke E M van Erp, Melissa H S Hillebrandt-Roeffen, Laurens van Houdt, Emmy D G Fleuren, Winette T A van der Graaf, Yvonne M H Versleijen-Jonkers
BACKGROUND: The receptor tyrosine kinase (RTK) anaplastic lymphoma kinase (ALK) has been implicated in the tumorigenesis of rhabdomyosarcoma (RMS). However, the exact role of ALK in RMS is debatable and remains to be elucidated. OBJECTIVE: To determine the in vitro and in vivo effects and mechanism of action of the second-generation ALK inhibitor ceritinib on RMS cell growth. METHODS: Effects of ceritinib on cell proliferation, wound healing, cell cycle, and RTK signaling were determined in alveolar and embryonal rhabdomyosarcoma (ARMS, ERMS)...
October 24, 2017: Targeted Oncology
https://www.readbyqxmd.com/read/29061835/clinical-efficacy-of-alectinib-in-patients-with-alk-rearranged-non-small-cell-lung-cancer-after-ceritinib-failure
#17
Yuko Oya, Tatsuya Yoshida, Hiroaki Kuroda, Junichi Shimizu, Yoshitsugu Horio, Yukinori Sakao, Toyoaki Hida, Yasushi Yatabe
Several second-generation inhibitors of anaplastic lymphoma kinase (ALK) have demonstrated potent activity in ALK rearrangement-positive non-small cell lung cancer (NSCLC). Two of these agents, ceritinib, and alectinib, recently received approval for the treatment of ALK-rearranged NSCLC in Japan. The efficacy of treatment with a second-generation ALK inhibitor after failure with a different second-generation ALK inhibitor remains unclear. We present a series of eight patients with ALK-rearranged NSCLC treated with alectinib who experienced disease progression after ceritinib...
November 2017: Anticancer Research
https://www.readbyqxmd.com/read/29048652/activation-of-src-signaling-mediates-acquired-resistance-to-alk-inhibition-in-lung-cancer
#18
Ryohei Yoshida, Takaaki Sasaki, Yoshinori Minami, Yukiko Hibino, Shunsuke Okumura, Masatoshi Sado, Naoyuki Miyokawa, Satoshi Hayashi, Masahiro Kitada, Yoshinobu Ohsaki
Anaplastic lymphoma kinase (ALK) fusion oncogenes occur in approximately 3-5% of non-small cell lung cancer (NSCLC) cases. Various ALK inhibitors are in clinical use for the treatment of ALK-NSCLC, including the first generation ALK inhibitor, crizotinib, and recently the more highly potent alectinib and ceritinib. However, most tumors eventually become resistant to ALK specific inhibitors. To address the mechanisms underlying the development of ALK inhibitor resistance, we used iTRAQ quantitative mass spectrometry and phosphor-receptor tyrosine kinase arrays to investigate intracellular signaling alterations in ALK inhibitor resistant NSCLC cell lines...
September 28, 2017: International Journal of Oncology
https://www.readbyqxmd.com/read/29045271/rhabdomyosarcoma-cells-are-susceptible-to-cell-death-by-ldk378-alone-or-in-combination-with-sorafenib-independently-of-anaplastic-lymphoma-kinase-status
#19
Nadezda Dolgikh, Simone Fulda
Anaplastic lymphoma kinase (ALK) is a receptor tyrosine kinase that is often overexpressed in rhabdomyosarcoma (RMS). However, its oncogenic and functional role in RMS remains unclear. Therefore, we investigated the antitumor activity of LDK378 (ceritinib), a new second-generation ALK inhibitor approved for patients with ALK-positive non-small-cell lung cancers. Here, we report that LDK378 reduces cell viability and induces cell death in RMS cell lines at low micromolar IC50 concentrations irrespective of ALK expression levels or phosphorylation status...
November 2017: Anti-cancer Drugs
https://www.readbyqxmd.com/read/29034773/substrate-dependent-effects-of-molecular-targeted-anticancer-agents-on-activity-of-organic-anion-transporting-polypeptide-1b1
#20
Hiroyoshi Koide, Masayuki Tsujimoto, Ai Takeuchi, Miyu Tanaka, Yoko Ikegami, Mayu Tagami, Syoko Abe, Miki Hashimoto, Tetsuya Minegaki, Kohshi Nishiguchi
1. Organic anion-transporting polypeptide 1B1 (OATP1B1) plays an important role in the hepatic uptake of a broad range of substrate drugs. In vitro experiments show that molecular-targeted agents do not always have similar effects on OATP1B1 activity. 2. The purpose of this study was to clarify whether the effects of molecular-targeted agents on OATP1B1 are substrate-dependent. We used OATP1B1-transfected cells to compare the effects of molecular-targeted agents on OATP1B1-mediated uptake of fluorescein (FL), 2',7'-dichlorofluorescein (DCF), atorvastatin, SN-38, and valsartan...
October 16, 2017: Xenobiotica; the Fate of Foreign Compounds in Biological Systems
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