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Azd9291

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https://www.readbyqxmd.com/read/28765329/overcoming-acquired-resistance-to-azd9291-a-third-generation-egfr-inhibitor-through-modulation-of-mek-erk-dependent-bim-and-mcl-1-degradation
#1
Puyu Shi, You-Take Oh, Liang Deng, Guojing Zhang, Guoqing Qian, Shuo Zhang, Hui Ren, Grant Wu, Benjamin Legendre, Emily Anderson, Suresh S Ramalingam, Taofeek K Owonikoko, Mingwei Chen, Shi-Yong Sun
<p>The mechanisms accounting for anticancer activity of AZD9291 (osimertinib or TAGRISSO™), an approved third generation EGFR inhibitor, in EGFR-mutant non-small cell lung cancer (NSCLC) cells and particularly for the subsequent development of acquired resistance are unclear and thus are the focus of this study.</p> <br /><br />Experimental Design: <p>AZD9219-resistant cell lines were established by exposing sensitive cell lines to AZD9291. Protein alterations were detected with Western blotting...
August 1, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/28730963/increased-expression-of-ire1%C3%AE-associates-with-the-resistant-mechanism-of-osimertinib-azd9291-resistant-non-small-cell-lung-cancer-hcc827-osir-cells
#2
Zheng-Hai Tang, Min-Xia Su, Xia Guo, Xiao-Ming Jiang, Lin Jia, Xiuping Chen, Jin-Jian Lu
BACKGROUND: Osimertinib (OSI), also known as AZD9291, is a third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) that has been approved for the treatment of non-small cell lung cancer (NSCLC) patients. OBJECTIVE: Establishment of the OSI-resistant HCC827/OSIR cell line and study of its resistant mechanism. METHOD: The anti-proliferative effect was studied through MTT and colony formation assays. The protein expression was detected by Western blot assay...
July 19, 2017: Anti-cancer Agents in Medicinal Chemistry
https://www.readbyqxmd.com/read/28577957/egfr-t790m-mutation-testing-within-the-osimertinib-aura-phase-i-study
#3
Simon Dearden, Helen Brown, Suzanne Jenkins, Kenneth S Thress, Mireille Cantarini, Rebecca Cole, Malcolm Ranson, Pasi A Jänne
OBJECTIVES: Reliable epidermal growth factor receptor (EGFR) mutation testing techniques are required to identify eligible patients with EGFR mutation/T790M positive advanced non-small cell lung cancer (NSCLC), for treatment with osimertinib (AZD9291), an oral, potent, irreversible EGFR tyrosine kinase inhibitor (TKI) selective for EGFR-TKI-sensitizing and T790M resistance mutations over wild-type EGFR. There is no current consensus regarding the best method to detect EGFR T790M mutations...
July 2017: Lung Cancer: Journal of the International Association for the Study of Lung Cancer
https://www.readbyqxmd.com/read/28566331/pharmacokinetics-and-drug-interactions-determine-optimum-combination-strategies-in-computational-models-of-cancer-evolution
#4
Shaon Chakrabarti, Franziska Michor
The identification of optimal drug administration schedules to battle the emergence of resistance is a major challenge in cancer research. The existence of a multitude of resistance mechanisms necessitates administering drugs in combination, significantly complicating the endeavor of predicting the evolutionary dynamics of cancers and optimal intervention strategies. A thorough understanding of the important determinants of cancer evolution under combination therapies is therefore crucial for correctly predicting treatment outcomes...
July 15, 2017: Cancer Research
https://www.readbyqxmd.com/read/28456628/structural-pharmacological-studies-on-egfr-t790m-c797s
#5
Lu-Lu Kong, Rui Ma, Ming-Yu Yao, Xiao-E Yan, Su-Jie Zhu, Peng Zhao, Cai-Hong Yun
Drug-resistance is a major challenge in targeted therapy of EGFR mutated non-small cell lung cancers (NSCLCs). The third-generation irreversible inhibitors such as AZD9291, CO-1686 and WZ4002 can overcome EGFR T790M drug-resistance mutant through covalent binding through Cys 797, but ultimately lose their efficacy upon emergence of the new mutation C797S. To develop new reversible inhibitors not relying on covalent binding through Cys 797 is therefore urgently demanded. Gö6976 is a staurosporine-like reversible inhibitor targeting T790M while sparing the wild-type EGFR...
April 26, 2017: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/28426996/design-synthesis-sar-discussion-in%C3%A2-vitro-and-in%C3%A2-vivo-evaluation-of-novel-selective-egfr-modulator-to-inhibit-l858r-t790m-double-mutants
#6
Haoyang Zhang, Wenkui Wu, Chao Feng, Zhaogang Liu, Enhe Bai, Xueyuan Wang, Meng Lei, Hao Cheng, Huayun Feng, Jingmiao Shi, Jia Wang, Zhao Zhang, Tao Jin, Shanshan Chen, Shihe Hu, Yongqiang Zhu
Based upon the modeling binding mode of marketed AZD9291 with T790M, a series of 5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinoline derivatives were designed and synthesized with the purpose to overcome the drug resistance resulted from T790M/L858R double mutations. The most potent compound 8 showed excellent enzyme inhibitory activities and selectivity with sub nanomolar IC50 values for both the single L858R and double T790M/L858R mutant EGFRs, and was more than 8-fold selective for wild type EGFR. Compound 8 exhibited good microsomes stabilities and pharmacokinetic properties and lower binding affinity to hERG ion channel than AZD9291 and displayed strong antiproliferative activity against the H1975 non-small cell lung cancer (NSCLC) cells bearing T790M/L858R and in vivo anticancer efficacy in a human NSCLC (H1975) xenograft mouse model...
April 14, 2017: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28422737/generation-of-lung-cancer-cell-lines-harboring-egfr-t790m-mutation-by-crispr-cas9-mediated-genome-editing
#7
Mi-Young Park, Min Hee Jung, Eun Young Eo, Seokjoong Kim, Sang Hoon Lee, Yeon Joo Lee, Jong Sun Park, Young Jae Cho, Jin Haeng Chung, Cheol Hyeon Kim, Ho Il Yoon, Jae Ho Lee, Choon-Taek Lee
Tyrosine kinase inhibitors (TKIs) such as gefitinib and erlotinib are effective against lung adenocarcinomas harboring epidermal growth factor receptor (EGFR) mutations. However, cancer cells can develop resistance to these agents with prolonged exposure; in over 50% of cases, this is attributable to the EGFR T790M mutation. Moreover, additional resistance mutations can arise with the use of new drugs. Cancer cell lines with specific mutations can enable the study of resistance mechanisms. In this study, we introduced the EGFR T790M mutation into the PC9 human lung cancer cell line-which has a deletion in exon 19 of the EGFR gene-by clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated (Cas)9-mediated genome editing...
May 30, 2017: Oncotarget
https://www.readbyqxmd.com/read/28367058/epidermal-growth-factor-receptor-t790m-mutation-positive-metastatic-non-small-cell-lung-cancer-focus-on-osimertinib-azd9291
#8
REVIEW
Nibal Saad, Aarati Poudel, Alina Basnet, Ajeet Gajra
Adenocarcinoma is the most common type of non-small-cell lung cancer (NSCLC). Adenocarcinoma with epidermal growth factor receptor (EGFR) mutations accounts for 8%-30% of all cases of NSCLC depending on the geography and ethnicity. EGFR-mutated NSCLC usually responds to first-line therapy with EGFR tyrosine kinase inhibitors (TKIs). However, there is eventual loss of efficacy to TKIs due to development of resistance. The most frequent cause for resistance is a second EGFR mutation in exon 20 (T790M), which is encountered in up to 62% of patients...
2017: OncoTargets and Therapy
https://www.readbyqxmd.com/read/28341106/the-apple-trial-feasibility-and-activity-of-azd9291-osimertinib-treatment-on-positive-plasma-t790m-in-egfr-mutant-nsclc-patients-eortc-1613
#9
Jordi Remon, Jessica Menis, Baktiar Hasan, Aleksandra Peric, Eleonora De Maio, Silvia Novello, Martin Reck, Thierry Berghmans, Bartosz Wasag, Benjamin Besse, Rafal Dziadziuszko
The AZD9291 (Osimertinib) Treatment on Positive PLasma T790M in EGFR-mutant NSCLC Patients (APPLE) trial is a randomized, open-label, multicenter, 3-arm, phase II study in advanced, epidermal growth factor receptor (EGFR)-mutant and EGFR tyrosine kinase inhibitor (TKI)-naive non-small-cell lung cancer (NSCLC) patients, to evaluate the best strategy for sequencing gefitinib and osimertinib treatment. Advanced EGFR-mutant NSCLC patients, with World Health Organization performance status 0-2 who are EGFR TKI treatment-naive and eligible to receive first-line treatment with EGFR TKI will be randomized to: In all arms, a plasmatic ctDNA T790M test will be performed by a central laboratory at the Medical University of Gdansk (Poland) but will be applied as a predictive marker for making treatment decisions only in arm B...
March 1, 2017: Clinical Lung Cancer
https://www.readbyqxmd.com/read/28237877/osimertinib-induces-autophagy-and-apoptosis-via-reactive-oxygen-species-generation-in-non-small-cell-lung-cancer-cells
#10
Zheng-Hai Tang, Wen-Xiang Cao, Min-Xia Su, Xiuping Chen, Jin-Jian Lu
Osimertinib (OSI), also known as AZD9291, is a third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor that has been approved for the treatment of non-small cell lung cancer (NSCLC) patients harboring EGFR T790M mutation. Herein, we indicated for the first time that OSI increased the accumulations of cytoplasmic vacuoles, the expression of phosphatidylethanolamine-modified microtubule-associated protein light-chain 3 (LC3-II), and the formation of GFP-LC3 puncta in various cancer cells...
April 15, 2017: Toxicology and Applied Pharmacology
https://www.readbyqxmd.com/read/28219203/-precision-first-line-therapy-for-advanced-non-small-cell-lung-cancer-patients-harboring-egfr-mutation
#11
D M Yuan, Y Song
Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) have become the preferred treatment option for advanced non-small-cell lung cancer (NSCLC) patients with activating mutations in epidermal growth factor receptor (EGFR) according to major practice guidelines. Gefitinib, elortinib and icotinib formed the cornerstone of first-line EGFR-TKIs in the clinical practice in our country. Now, with the continuously emerging of new types of EGFR-TKIs and ever-increasing publication of clinical trial results on afatinib, AZD9291 and other TKIs, we have more first-line choices for patients with EGFR mutations...
February 23, 2017: Zhonghua Zhong Liu za Zhi [Chinese Journal of Oncology]
https://www.readbyqxmd.com/read/28061471/transformation-to-small-cell-carcinoma-as-an-acquired-resistance-mechanism-to-azd9291-a-case-report
#12
Lin Li, Hui Wang, Chao Li, Zheng Wang, Ping Zhang, Xu Yan
AZD9291, a third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI), benefits patients with T790M mutant non-small-cell lung cancer who fail treatment with first-generation EGFR TKIs. Acquisition of resistance to AZD9291 occurs inevitable and mechanisms need to be explored. We reported an advanced lung adenocarcinoma female with EGFR exon19 deletion treated on AZD9291 after failure of erlotinib and chemotherapy. Disease progressed again after 6 months' treatment of AZD9291 with hepatic metastasis...
March 14, 2017: Oncotarget
https://www.readbyqxmd.com/read/28029074/a-rational-approach-to-target-the-epidermal-growth-factor-receptor-in-glioblas
#13
Madan M Kwatra
Glioblastoma (GBM) is a deadly brain cancer, and all attempts to control it have failed so far. However, the future looks bright, as we now know the molecular landscape of GBM through the work of The Cancer Genome Atlas (TCGA) program. GBMs exhibit significant inter- and intra-tumoral heterogeneity, and to control this type of tumor, a personalized approach is required. One target, whose gene is amplified and mutated in a large number of GBMs, is the epidermal growth factor receptor (EGFR). But all attempts to target it have been unsuccessful...
December 26, 2016: Current Cancer Drug Targets
https://www.readbyqxmd.com/read/28009438/population-pharmacokinetics-and-exposure-response-of-osimertinib-in-patients-with-non-small-cell-lung-cancer
#14
Kathryn Brown, Craig Comisar, Han Witjes, John Maringwa, Rik de Greef, Karthick Vishwanathan, Mireille Cantarini, Eugène Cox
AIMS: To develop a population (pop) pharmacokinetic (PK) model for osimertinib (AZD9291) and its metabolite (AZ5104) and investigate the exposure-response relationships for selected efficacy and safety parameters. METHODS: PK, safety and efficacy data were collected from two non-small cell lung cancer (NSCLC) patient studies (n = 748) and one healthy volunteer study (n = 32), after single or multiple once-daily dosing of 20-240 mg osimertinib. Nonlinear mixed effects modelling was used to characterise the popPK...
June 2017: British Journal of Clinical Pharmacology
https://www.readbyqxmd.com/read/27923714/acquired-braf-v600e-mutation-as-resistant-mechanism-after-treatment-with-osimertinib
#15
Chao-Chi Ho, Wei-Yu Liao, Chih-An Lin, Jin-Yuan Shih, Chong-Jen Yu, James Chih-Hsin Yang
INTRODUCTION: AZD9291 (osimertinib) is designed for acquired T790M mutation after first- and second-generation EGFR) tyrosine kinase inhibitors have been used. Some of the resistance mechanisms that present after osimertinib treatment, including a newly acquired EGFR C797S mutation, have been identified. It is unclear, however, whether the bypass pathway is also a mechanism of resistance in patients after osimertinib treatment. METHODS: Cells from malignant pleural effusion were collected and cultured at the time of progression in a patient being treated with osimertinib...
March 2017: Journal of Thoracic Oncology
https://www.readbyqxmd.com/read/27885838/osimertinib-for-egfr-t790m-mutation-positive-non-small-cell-lung-cancer
#16
REVIEW
Kenzo Soejima, Hiroyuki Yasuda, Toshiyuki Hirano
Significant advances have been made since the development of epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) targeting EGFR mutations in non-small-cell lung cancer (NSCLC), however, lung cancer cells eventually acquire resistance to those agents. Osimertinib (AZD9291) has been developed as 3(rd) generation EGFR-TKI with activities against sensitizing mutations and T790 M resistance mutation, which account for about 50% of the mechanisms of acquired resistance to 1(st) or 2(nd) generation EGFR-TKIs...
January 2017: Expert Review of Clinical Pharmacology
https://www.readbyqxmd.com/read/27861144/inhibition-of-oxidative-phosphorylation-suppresses-the-development-of-osimertinib-resistance-in-a-preclinical-model-of-egfr-driven-lung-adenocarcinoma
#17
Matthew J Martin, Cath Eberlein, Molly Taylor, Susan Ashton, David Robinson, Darren Cross
Metabolic plasticity is an emerging hallmark of cancer, and increased glycolysis is often observed in transformed cells. Small molecule inhibitors that target driver oncogenes can potentially inhibit the glycolytic pathway. Osimertinib (AZD9291) is a novel EGFR tyrosine kinase inhibitor (TKI) that is potent and selective for sensitising (EGFRm) and T790M resistance mutations. Clinical studies have shown osimertinib to be efficacious in patients with EGFRm/ T790M advanced NSCLC who have progressed after EGFR-TKI treatment...
December 27, 2016: Oncotarget
https://www.readbyqxmd.com/read/27835594/characterization-of-osimertinib-azd9291-resistant-non-small-cell-lung-cancer-nci-h1975-osir-cell-line
#18
Zheng-Hai Tang, Xiao-Ming Jiang, Xia Guo, Chi Man Vivienne Fong, Xiuping Chen, Jin-Jian Lu
Osimertinib (OSI, also known as AZD9291) is the newest FDA-approved epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor for non-small cell lung cancer (NSCLC) patients with EGFR T790M mutation. However, resistance to OSI is likely to progress and the study of potential OSI-resistant mechanisms in advanced is necessary. Here, the OSI-resistant NCI-H1975/OSIR cells were established. After cells developed resistance to OSI, cell proliferation was decreased while cell migration and invasion were increased...
December 6, 2016: Oncotarget
https://www.readbyqxmd.com/read/27821604/targeting-the-gatekeeper-osimertinib-in-egfr-t790m-mutation-positive-non-small-cell-lung-cancer
#19
Ferdinandos Skoulidis, Vassiliki A Papadimitrakopoulou
In 2015, the FDA approved an unprecedented number of new therapies for non-small cell lung cancer (NSCLC), among them therapies addressing specific genomic tumor subsets in the setting of development of resistance to first-line targeted therapy. Osimertinib (Tagrisso, formerly AZD9291; AstraZeneca) is indicated for patients with metastatic EGFR T790M mutation-positive NSCLC, as detected by an FDA-approved test, who have progressed on or after EGFR tyrosine kinase inhibitor therapy. It received breakthrough therapy designation, priority review status, and accelerated approval from the FDA...
February 1, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/27793905/isoflavone-extracts-enhance-the-effect-of-epidermal-growth-factor-receptor-inhibitors-in-nsclc-cell-lines
#20
Rita Ambrosio, Maria Neve Ombra, Cesare Gridelli, Gianluca Picariello, Michele DI Stasio, Maria G Volpe
AIM: We investigated the effects of the pharmacological inhibition in vitro of epidermal growth factor receptor (EGFR) in combination with isoflavones. MATERIALS AND METHODS: Four anticancer drugs (erlotinib, gefitinib, afatinib and AZD9291) were combined with soy and red clover isoflavone extracts and used in cellular proliferation assays. The antitumor activity of inhibitors alone and in combination with isoflavone extracts was compared on three non-small cell lung cancer (NSCLC) cell lines with affiant EGFR genotype: A549 (EGFR wt); H1795 (EGFR T790M); HCC827 (EGFR del E746-A750)...
2016: Anticancer Research
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