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https://www.readbyqxmd.com/read/28716641/synthesis-and-evaluation-of-osimertinib-derivatives-as-potent-egfr-inhibitors
#1
Hongying Gao, Zimo Yang, Xinglin Yang, Yu Rao
Osimertinib has been identified as a promising therapeutic drug targeting for EGFR T790M mutant non-small cell lung cancer (NSCLC). A new series of N-oxidized and fluorinated osimertinib derivatives were designed and synthesized. The cellular anti-proliferative activity, kinase inhibitory activity and the activation of EGFR signaling pathways of 1-6 in vitro were determined against L858R/T790M and wild-type EGFR, the antitumor efficacy in NCI-H1975 xenografts in vivo were further studied. Compound 2, the newly synthesized N-oxide metabolite in N,N,N'-trimethylethylenediamine side chain of osimertinib, showed a comparable kinase selectivity in vitro and a slightly better antitumor efficacy in vivo to osimertinib, making it valuable and suitable for the potential lung cancer therapy...
July 8, 2017: Bioorganic & Medicinal Chemistry
https://www.readbyqxmd.com/read/28710746/osimertinib-a-review-in-t790m-positive-advanced-non-small-cell-lung-cancer
#2
REVIEW
Yvette N Lamb, Lesley J Scott
Osimertinib (Tagrisso™) is an oral, CNS-active, third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) that targets EGFR TKI-sensitizing mutations and, crucially, the T790M mutation that often underlies acquired resistance to EGFR TKI therapy. Osimertinib has been approved in numerous countries for use in patients with T790M-positive advanced NSCLC. In the pivotal, international AURA3 trial in patients with T790M-positive advanced NSCLC who had disease progression after EGFR TKI therapy, osimertinib treatment significantly prolonged progression-free survival (PFS; primary endpoint) compared with platinum-pemetrexed therapy at the time of the primary analysis...
July 14, 2017: Targeted Oncology
https://www.readbyqxmd.com/read/28708233/treatment-in-egfr-mutated-non-small-cell-lung-cancer-how-to-block-the-receptor-and-overcome-resistance-mechanisms
#3
Claudia Proto, Giuseppe Lo Russo, Giulia Corrao, Monica Ganzinelli, Francesco Facchinetti, Roberta Minari, Marcello Tiseo, Marina Chiara Garassino
In non-small cell lung cancer (NSCLC), the identification of epidermal growth factor receptor (EGFR) mutations and the parallel development of EGFR tyrosine kinase inhibitors (TKIs) have radically changed the therapeutic management strategies. Currently, erlotinib, gefitinib, and afatinib are all approved as standard first-line treatment in EGFR-mutated NSCLC. However, despite the proven efficacy, some EGFR-mutated NSCLCs do not respond to EGFR TKIs, while some patients, after a favorable and prolonged response to EGFR TKIs, inevitably progress within about 10-14 months...
July 1, 2017: Tumori
https://www.readbyqxmd.com/read/28701107/overcoming-resistance-to-egfr-tyrosine-kinase-inhibitors-in-lung-cancer-focusing-on-non-t790m-mechanisms
#4
Kenichi Suda, Christopher J Rivard, Tetsuya Mitsudomi, Fred R Hirsch
Despite initial dramatic efficacy of EGFR tyrosine kinase inhibitors (TKIs) in EGFR-mutant lung cancer patients, emergence of acquired resistance is almost inevitable. The EGFR T790M secondary mutation that accounts for ~50% of resistance is now treatable with osimertinib. However, for the remaining 50% of patients who develop resistance mechanisms other than T790M mutation, cytotoxic chemotherapies are still the standard of care and novel treatment strategies are urgently needed. Areas covered: In this review, we discuss current experimental and clinical evidence to develop better treatment strategies to overcome or prevent acquired resistance to EGFR-TKIs in lung cancers, focusing on non-T790M mechanisms...
July 13, 2017: Expert Review of Anticancer Therapy
https://www.readbyqxmd.com/read/28699260/australian-recommendations-for-egfr-t790m-testing-in-advanced-non-small-cell-lung-cancer
#5
REVIEW
Thomas John, Jeffrey J Bowden, Stephen Clarke, Stephen B Fox, Kerryn Garrett, Keith Horwood, Christos S Karapetis
First-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are used as first-line therapy in patients with non-small cell lung cancer (NSCLC) harboring a sensitizing mutation in the EGFR gene. Unfortunately, resistance to these therapies often occurs within 10 months of commencing treatment and is mostly commonly due to the development of the EGFR T790M mutation. Treatment with the third-generation EGFR TKI, osimertinib can prolong progression free survival in patients with the T790M mutation, so it is important to determine the resistance mechanism in order to plan ongoing therapeutic strategies...
July 12, 2017: Asia-Pacific Journal of Clinical Oncology
https://www.readbyqxmd.com/read/28680534/nsclc-depend-upon-yap-expression-and-nuclear-localization-after-acquiring-resistance-to-egfr-inhibitors
#6
Marc McGowan, Lilach Kleinberg, Ann Rita Halvorsen, Åslaug Helland, Odd Terje Brustugun
Yes-associated protein (YAP) is a downstream target of the Hippo pathway and has been found to be oncogenic driving many cancers into developing metastatic phenotypes leading to poor survival outcomes. This study investigated if YAP expression is associated with drug resistance in two non-small cell lung cancer (NSCLC) lines (HCC827 and H1975) generated to become resistant to the EGFR tyrosine kinase inhibitors (EGFR TKI) erlotinib, gefitinib or the T790M-specific osimertinib. We found that acquired EGFR TKI resistance was associated with YAP over-expression (osimertinib-resistant cells) or YAP amplification (erlotinib- and gefitinib-resistant cells) along with EMT phenotypic changes...
March 2017: Genes & Cancer
https://www.readbyqxmd.com/read/28676222/optimal-management-of-egfr-mutant-non-small-cell-lung-cancer-with-disease-progression-on-first-line-tyrosine-kinase-inhibitor-therapy
#7
REVIEW
Bin-Chi Liao, Chia-Chi Lin, Jih-Hsiang Lee, James Chih-Hsin Yang
The first-generation epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs), gefitinib and erlotinib, and the second-generation EGFR-TKI, afatinib, have all been approved as standard first-line treatments for advanced EGFR-mutant non-small cell lung cancer (NSCLC) based on superior progression-free survival results compared to platinum doublet chemotherapy regimens. Acquired resistance to an EGFR-TKI inevitably develops after a period of effective drug treatment. After tumor progression, many combination therapy regimens that include an EGFR-TKI, or EGFR-TKI monotherapy, have been tested in prospective trials with the aim of extending survival...
August 2017: Lung Cancer: Journal of the International Association for the Study of Lung Cancer
https://www.readbyqxmd.com/read/28662863/brief-report-lung-adenocarcinoma-harboring-egfr-t790m-and-in-trans-c797s-responds-to-combination-therapy-of-first-and-third-generation-egfr-tkis-and-shifts-allelic-configuration-at-resistance
#8
Zhen Wang, Jin-Ji Yang, Jie Huang, Jun-Yi Ye, Xu-Chao Zhang, Hai-Yan Tu, Han Han-Zhang, Yi-Long Wu
INTRODUCTION: The efficacy of osimertinib was compromised by the development of resistance mechanisms, such as EGFR C797S. In vitro study proved that cells harboring EGFR C797S in trans with T790M are sensitive to a combination of first and third generation epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs). However, this has not been reported clinically. METHODS: We performed capture-based sequencing on longitudinal plasma samples obtained at various treatment milestones from an advanced lung adenocarcinoma patient undergoing targeted therapy...
June 26, 2017: Journal of Thoracic Oncology
https://www.readbyqxmd.com/read/28625657/synergy-between-next-generation-egfr-tyrosine-kinase-inhibitors-and-mir-34a-in-the-inhibition-of-non-small-cell-lung-cancer
#9
Jane Zhao, Adriana Guerrero, Kevin Kelnar, Heidi J Peltier, Andreas G Bader
OBJECTIVES: EGFR tyrosine kinase inhibitors (TKIs) are widely used to treat NSCLC, primarily patients with activating mutations, with more limited response in wild-type disease. However, even with EGFR-mutated disease, many patients fail to respond, most who initially respond fail to respond completely, and almost all develop resistance and inevitably progress. New therapeutic options that improve these outcomes could provide substantial clinical benefit. We previously demonstrated strong synergistic effects between erlotinib and the tumor suppressor microRNA miR-34a, sensitizing NSCLC cells with primary resistance (EGFR wild-type) and restoring sensitivity in cells with acquired resistance...
June 2017: Lung Cancer: Journal of the International Association for the Study of Lung Cancer
https://www.readbyqxmd.com/read/28625644/treatment-options-for-egfr-mutant-nsclc-with-cns-involvement-can-patients-bloom-with-the-use-of-next-generation-egfr-tkis
#10
REVIEW
Chee-Seng Tan, Byoung Chul Cho, Ross A Soo
With the use of EGFR TKIs, patient survival is now prolonged and as a consequence, a higher chance of development of CNS metastases has been observed during the course of the disease. CNS metastases remains a therapeutically challenging subset of patient to treat owing to the blood-brain barrier (BBB). Prior to routine EGFR mutation testing, surgical resection, stereotactic radiosurgery and/or whole brain radiation therapy (WBRT) were the main treatment options whereas treatment options for patients with leptomeningeal metastases (LM) included intra-thecal chemotherapy, WBRT, and ventriculo-peritoneal shunting...
June 2017: Lung Cancer: Journal of the International Association for the Study of Lung Cancer
https://www.readbyqxmd.com/read/28625643/sequential-liquid-biopsies-reveal-dynamic-alterations-of-egfr-driver-mutations-and-indicate-egfr-amplification-as-a-new-mechanism-of-resistance-to-osimertinib-in-nsclc
#11
Franciele H Knebel, Fabiana Bettoni, Andrea K Shimada, Manoel Cruz, João Victor Alessi, Marcelo V Negrão, Luiz Fernando L Reis, Artur Katz, Anamaria A Camargo
Osimertinib is an EGFR-T790M-specific TKI, which has demonstrated impressive response rates in NSCLC, after failure to first-line anti-EGFR TKIs. However, acquired resistance to osimertinib is also observed and the molecular mechanisms of resistance are not yet fully understood. Monitoring and managing NSCLC patients who progressed on osimertinib is, therefore, emerging as an important clinical challenge. Sequential liquid biopsies were used to monitor a patient with EGFR-exon19del positive NSCLC, who received erlotinib and progressed through the acquisition of the EGFR-T790M mutation...
June 2017: Lung Cancer: Journal of the International Association for the Study of Lung Cancer
https://www.readbyqxmd.com/read/28625641/emergence-of-novel-and-dominant-acquired-egfr-solvent-front-mutations-at-gly796-g796s-r-together-with-c797s-r-and-l792f-h-mutations-in-one-egfr-l858r-t790m-nsclc-patient-who-progressed-on-osimertinib
#12
Sai-Hong Ignatius Ou, Jean Cui, Alexa B Schrock, Michael E Goldberg, Viola W Zhu, Lee Albacker, Philip J Stephens, Vincent A Miller, Siraj M Ali
Acquired epidermal growth factor receptor (EGFR) resistance mutations to osimertinib are common, including the EGFR C797S that abolishes the covalent binding of osimertinib to EGFR. Here we report the emergence of novel EGFR solvent front mutations at Gly796 (G796S/R) in addition to a hinge pocket L792F/H mutations, and C797S/G all in cis with T790M in a single patient on progression on osimertinib as detected by plasma circulating tumor DNA (ctDNA) assay in the course of clinical care. A 69-year-old Caucasian female former light-smoker presented with stage IV EGFR L858R positive adenocarcinoma who developed EGFR T790M mutation after 8 month treatment of erlotinib...
June 2017: Lung Cancer: Journal of the International Association for the Study of Lung Cancer
https://www.readbyqxmd.com/read/28620581/third-generation-tyrosine-kinase-inhibitors-targeting-epidermal-growth-factor-receptor-mutations-in-non-small-cell-lung-cancer
#13
REVIEW
Tristan A Barnes, Grainne M O'Kane, Mark David Vincent, Natasha B Leighl
Sensitizing mutations in the epidermal growth factor receptor (EGFR) predict response to EGFR tyrosine kinase inhibitors (TKIs) and both first- and second-generation TKIs are available as first-line treatment options in patients with advanced EGFR-mutant non-small cell lung cancer. Eventual resistance develops with multiple mechanisms identifiable both upon repeat biopsy and in plasma circulating tumor DNA. The T790M gatekeeper mutation is responsible for almost 60% of cases. A number of third-generation TKIs are in clinical development, and osimertinib has been approved by the US Food and Drug Administration for the treatment of patients with EGFR T790M mutant lung cancer after failure of initial EGFR kinase therapy...
2017: Frontiers in Oncology
https://www.readbyqxmd.com/read/28616379/re-biopsy-after-relapse-of-targeted-therapy-t790m-after-epidermal-growth-factor-mutation-where-and-why-based-on-a-case-series
#14
Paul Zarogoulidis, Aggeliki Rapti, Chrysanthi Sardeli, Panagiotis Chinelis, Anastasia Athanasiadou, Katerina Paraskevaidou, Anastasios Kallianos, Lemonia Veletza, Georgia Trakada, Wolfgang Hohenforst-Schmidt, Haidong Huang
Guidelines for the treatment of non-small cell lung cancer adenocarcinoma positive in epidermal growth factor mutations indicate tyrosine kinase inhibitors. There are currently three tyrosine kinase inhibitors that can be used as first line treatment: gefitinib, erlotinib and afatinib. Regarding erlotinib and afatinib dosage can be modified in the case of severe adverse effects. In the case of disease relapse investigation for T790M mutation has to be made either with re-biopsy or liquid biopsy and osimertinib has to be administered when T790M is diagnosed...
2017: Respiratory Medicine Case Reports
https://www.readbyqxmd.com/read/28607578/osimertinib-in-patients-with-advanced-epidermal-growth-factor-receptor-t790m-mutation-positive-non-small-cell-lung-cancer-rationale-evidence-and-place-in-therapy
#15
REVIEW
Biagio Ricciuti, Sara Baglivo, Luca Paglialunga, Andrea De Giglio, Guido Bellezza, Rita Chiari, Lucio Crinò, Giulio Metro
The identification of epidermal growth factor receptor (EGFR) mutations represented a fundamental step forward in the treatment of advanced non-small cell lung cancer (NSCLC) as they define a subset of patients who benefit from the administration of specifically designed targeted therapies. The inhibition of mutant EGFR through EGFR-tyrosine kinase inhibitors (TKIs), either reversible, first-generation gefitinib and erlotinib, or irreversible, second-generation afatinib, has dramatically improved the prognosis of patients harboring this specific genetic alteration, leading to unexpected clinical benefit...
June 2017: Therapeutic Advances in Medical Oncology
https://www.readbyqxmd.com/read/28603991/trisubstituted-pyridinylimidazoles-as-potent-inhibitors-of-the-clinically-resistant-l858r-t790m-c797s-egfr-mutant-targeting-of-both-hydrophobic-regions-and-the-phosphate-binding-site
#16
Marcel Günther, Jonas Lategahn, Michael Juchum, Eva Döring, Marina Keul, Julian Engel, Hannah L Tumbrink, Daniel Rauh, Stefan Laufer
Inhibition of the epidermal growth factor receptor represents one of the most promising strategies in the treatment of lung cancer. Acquired resistance compromises the clinical efficacy of EGFR inhibitors during long-term treatment. The recently discovered EGFR-C797S mutation causes resistance against third-generation EGFR inhibitors. Here we present a rational approach based on extending the inhibition profile of a p38 MAP kinase inhibitor toward mutant EGFR inhibition. We used a privileged scaffold with proven cellular potency as well as in vivo efficacy and low toxicity...
June 21, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28601918/osimertinib-reactivated-immune-related-colitis-after-treatment-with-anti-pd1-antibody-for-non-small-cell-lung-cancer
#17
Tomoyoshi Takenaka, Koji Yamazaki, Naoko Miura, Naohiko Harada, Sadanori Takeo
We reported a case of relapsing immune-related colitis (initially caused by nivolumab) following osimertinib therapy for lung adenocarcinoma. A 45-year-old female who had never smoked was diagnosed with adenocarcinoma of the lung and underwent surgical resection. Four years after surgical resection, she was diagnosed with recurrent disease and was eventually treated with nivolumab as third-line therapy. One month after the completion of nivolumab therapy, the patient reported abdominal pain and frequent diarrhea...
June 10, 2017: Investigational New Drugs
https://www.readbyqxmd.com/read/28577957/egfr-t790m-mutation-testing-within-the-osimertinib-aura-phase-i-study
#18
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/28572531/egfr-g796d-mutation-mediates-resistance-to-osimertinib
#19
Di Zheng, Min Hu, Yu Bai, Xuehua Zhu, Xuesong Lu, Chunyan Wu, Jiying Wang, Li Liu, Zheng Wang, Jian Ni, Zhenfan Yang, Jianfang Xu
Osimertinib is an effective third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) approved in multiple countries and regions for patients with EGFR T790M mutation-positive non-small cell lung cancer (NSCLC). Despite impressive initial tumor responses, development of drug resistance ultimately limits the benefit of this compound. Mechanisms of resistance to osimertinib are just beginning to emerge, such as EGFR C797S and L718Q mutations, BRAF V600E and PIK3CA E545K mutations, as well as ERBB2 and MET amplification...
May 16, 2017: Oncotarget
https://www.readbyqxmd.com/read/28565936/osimertinib-a-third-generation-tyrosine-kinase-inhibitor-for-treatment-of-epidermal-growth-factor-receptor-mutated-non-small-cell-lung-cancer-with-the-acquired-thr790met-mutation
#20
Meredith K Bollinger, Amanda S Agnew, Gerard P Mascara
Osimertinib is a third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) approved for the treatment of metastatic EGFR T790M mutation-positive non-small cell lung cancer (NSCLC) in patients failing previous TKI therapy. The T790M mutation is an acquired resistance mechanism found in over half of patients with NSCLC progressing on first-generation TKIs. First- and second-generation TKIs do not inhibit the T790M mutation at clinically relevant concentrations. Osimertinib is selective for mutated forms of EGFR, including the TKI-sensitizing mutations L858R and exon 19 deletions, as well as the acquired T790M resistance mutation...
January 1, 2017: Journal of Oncology Pharmacy Practice
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