scholarly journals Inhibition of osimertinib-resistant epidermal growth factor receptor EGFR-T790M/C797S

2019 ◽  
Vol 10 (46) ◽  
pp. 10789-10801 ◽  
Author(s):  
Jonas Lategahn ◽  
Marina Keul ◽  
Philip Klövekorn ◽  
Hannah L. Tumbrink ◽  
Janina Niggenaber ◽  
...  
Keyword(s):  
Epidermal Growth Factor Receptor ◽  
Growth Factor Receptor ◽  
Binding Mode ◽  
Drug Resistant ◽  
X Ray ◽  
Covalent Inhibitors ◽  
Epidermal Growth ◽  
Resistant Mutants ◽  
Insight Into ◽  
Egfr T790m

We present inhibitors of drug resistant mutants of EGFR including T790M and C797S. In addition, we present the first X-ray crystal structures of covalent inhibitors in complex with C797S-mutated EGFR to gain insight into their binding mode.

Indazole-Based Covalent Inhibitors To Target Drug-Resistant Epidermal Growth Factor Receptor

2017 ◽  
Vol 60 (6) ◽  
pp. 2361-2372 ◽  
Author(s):  
Stefano Tomassi ◽  
Jonas Lategahn ◽  
Julian Engel ◽  
Marina Keul ◽  
Hannah L. Tumbrink ◽  
...  
Keyword(s):  
Epidermal Growth Factor Receptor ◽  
Growth Factor ◽  
Epidermal Growth Factor ◽  
Growth Factor Receptor ◽  
Drug Resistant ◽  
Target Drug ◽  
Covalent Inhibitors ◽  
Epidermal Growth

scholarly journals Development of epidermal growth factor receptor tyrosine kinase inhibitors against EGFR T790M. Mutation in non small-cell lung carcinoma

Open Medicine ◽  
2016 ◽  
Vol 11 (1) ◽  
pp. 68-77 ◽  
Author(s):  
Yuli Wang ◽  
Zhitao Guo ◽  
Yang Li ◽  
Qinghua Zhou
Keyword(s):  
Epidermal Growth Factor Receptor ◽  
Small Cell Lung Carcinoma ◽  
Acquired Resistance ◽  
Growth Factor Receptor ◽  
Small Cell ◽  
Small Cell Lung ◽  
T790m Mutation ◽  
Cell Lung Carcinoma ◽  
Epidermal Growth ◽  
Egfr T790m

AbstractIndividualized therapies targeting epidermal growth factor receptor (EGFR) mutations show promises for the treatment of non small-cell lung carcinoma (NSCLC). However, disease progression almost invariably occurs 1 year after tyrosine kinase inhibitor (TKI) treatment. The most prominent mechanism of acquired resistance involves the secondary EGFR mutation, namely EGFR T790M, which accounts for 50%–60% of resistant tumors. A large amount of studies have focused on the development of effective strategies to treat TKI-resistant EGFR T790M mutation in lung tumors. Novel generations of EGFR inhibitors are producing encouraging results in patients with acquired resistance against EGFR T790M mutation. This review will summarize the novel inhibitors, which might overcome resistance against EGFR T790M mutation.

scholarly journals Effect of double mutations T790M/L858R on conformation and drug-resistant mechanism of epidermal growth factor receptor explored by molecular dynamics simulations

RSC Advances ◽  
2018 ◽  
Vol 8 (70) ◽  
pp. 39797-39810 ◽  
Author(s):  
Fangfang Yan ◽  
Xinguo Liu ◽  
Shaolong Zhang ◽  
Jing Su ◽  
Qinggang Zhang ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Free Energy ◽  
Epidermal Growth Factor Receptor ◽  
Decomposition Method ◽  
Growth Factor Receptor ◽  
Drug Resistant ◽  
Energy Decomposition ◽  
Free Energy Decomposition ◽  
Epidermal Growth ◽  
Dynamics Simulations

The MM-GBSA method coupled with residue-based free energy decomposition method was performed to explore drug-resistant mechanisms of the mutated EGFR.

Multicenter Validation Study to Implement Plasma Epidermal Growth Factor Receptor T790M Testing in Clinical Laboratories

2020 ◽  
pp. 520-533 ◽  
Author(s):  
Natasha B. Leighl ◽  
Suzanne Kamel-Reid ◽  
Parneet K. Cheema ◽  
Janessa Laskin ◽  
Aly Karsan ◽  
...  
Keyword(s):  
Epidermal Growth Factor Receptor ◽  
Growth Factor ◽  
Epidermal Growth Factor ◽  
Validation Study ◽  
Growth Factor Receptor ◽  
Clinical Laboratories ◽  
Epidermal Growth ◽  
Positive Results ◽  
Egfr T790m ◽  
Multicenter Validation

PURPOSE Plasma detection of EGFR T790M mutations is an emerging alternative to tumor rebiopsy in acquired epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor resistance. Validation of analytical sensitivity and clinical utility is required before routine diagnostic use in clinical laboratories. PATIENTS AND METHODS Sixty-three patients with advanced EGFR-mutant lung cancer at 7 Canadian centers, who were being screened for the ASTRIS trial (ClinicalTrials.gov identifier: NCT02474355 ), participated in this companion study. Plasma T790M mutation was detected using droplet digital polymerase chain reaction, Cobas (Roche Diagnostics, Indianapolis, IN), or next-generation sequencing in 4 laboratories. T790M concordance was assessed between plasma and tumor samples. RESULTS Assessment of T790M in tumor biopsy tissue was successful in 81% of patients; 49% had confirmed T790M results (tumor or plasma) for ASTRIS. Plasma testing in this companion study yielded T790M results in 97% of patients; 62% had T790M-positive results, 36% had negative results, and 2% had indeterminate results. Of 38 patients with negative or indeterminate biopsy results, 55% had positive plasma T790M results, increasing the proportion with T790M-positive results to 73%. Sensitivity of plasma T790M testing was 75%. Overall concordance between tissue and plasma was 64%, and concordance among laboratories was 90.3%. Response to osimertinib and duration of therapy were similar irrespective of testing method (overall response rate, 62.5% for tissue, 66.7% for plasma, and 70.6% for both). CONCLUSION This multicenter validation study demonstrates that plasma EGFR T790M testing can identify significantly more patients than biopsy alone who may benefit from targeted therapy.

scholarly journals Osimertinib in the treatment of patients with epidermal growth factor receptor T790M mutation-positive metastatic non-small cell lung cancer: clinical trial evidence and experience

2016 ◽  
Vol 10 (6) ◽  
pp. 549-565 ◽  
Author(s):  
Ivana Sullivan ◽  
David Planchard
Keyword(s):  
Lung Cancer ◽  
Clinical Trial ◽  
Epidermal Growth Factor Receptor ◽  
Resistance Mutation ◽  
Growth Factor Receptor ◽  
Small Cell ◽  
Small Cell Lung ◽  
T790m Mutation ◽  
Epidermal Growth ◽  
Egfr T790m

Patients with advanced epidermal growth factor receptor ( EGFR) mutant non-small cell lung cancer (NSCLC) are particularly sensitive to treatment with first- or second-generation EGFR tyrosine kinase inhibitors such as gefitinib, erlotinib and afatinib, which block the cell-signaling pathways that drive the growth of tumor cells. Unfortunately, the majority of patients develop resistance to them after a median duration of response of around 10 months, and in over half of these patients the emergence of the EGFR T790M resistance mutation is detected. Osimertinib is an oral, highly selective, irreversible inhibitor of both EGFR-activating mutations and the T790M-resistance mutation, while sparing the activity of wild-type EGFR. This article reviews clinical trial development of osimertinib in patients with NSCLC, presenting efficacy and safety evidence for its value in the EGFR T790M mutation-positive population and in different settings, including patients with metastatic disease. The preclinical background of clinically acquired resistance to osimertinib is presented and the combination tactics being investigated in an attempt to circumvent this are addressed.

scholarly journals SYNTHESIS AND ANTICANCER SCREENING OF TRIAZINE ANALOGUES

2019 ◽  
pp. 114-121
Author(s):  
Anshuly Tiwari ◽  
Siddharth J. Modi ◽  
KAKASAHEB R MAHADIK ◽  
Mugdha R. Suryawanshi
Keyword(s):  
Epidermal Growth Factor Receptor ◽  
Molecular Docking ◽  
Growth Factor ◽  
Epidermal Growth Factor ◽  
Cell Lines ◽  
Growth Factor Receptor ◽  
Binding Mode ◽  
Spectroscopic Techniques ◽  
Epidermal Growth

Objective: The study was aimed to investigate the cytotoxic effect of S-5H-[1,2,4]-triazino (5,6-b) indol-3-yl-3,4-phenylethane-thioate derivatives as epidermal growth factor Receptor (EGFR) inhibitors. Methods: In the present study 14 novel triazine analogues were synthesized and characterized using different spectroscopic techniques such as FT-IR, NMR and Mass Spectroscopy. The anticancer activity was performed using MCF-7 (breast cancer) and K-562 (leukaemia) cell lines. Further, molecular docking was carried out using Vlife Molecular Docking Software (MDS) on crystal structure of epidermal growth factor receptor (EGFR) to identify the binding mode of interaction with an active site. Results: Compounds MA-7, MA-8, MA-12, MA-13 and MA-14 show potent activity against cancer cell lines in the range of<10 to 84.4 µg/ml. Further molecular docking on EGFR also supports that there is a strong correlation between in silico and in vitro biological activity. The results of this study may be further useful for lead optimization process. Conclusion: The results of this study indicates that the synthesized triazine analogues can give a potential lead as an anticancer agent.

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