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Brigatinib combined with anti-EGFR antibody overcomes osimertinib resistance in EGFR-mutated non-small-cell lung cancer
- Source :
- Nature Communications, Vol 8, Iss 1, Pp 1-16 (2017), Nature Communications
- Publication Year :
- 2017
- Publisher :
- Nature Portfolio, 2017.
-
Abstract
- Osimertinib has been demonstrated to overcome the epidermal growth factor receptor (EGFR)-T790M, the most relevant acquired resistance to first-generation EGFR–tyrosine kinase inhibitors (EGFR–TKIs). However, the C797S mutation, which impairs the covalent binding between the cysteine residue at position 797 of EGFR and osimertinib, induces resistance to osimertinib. Currently, there are no effective therapeutic strategies to overcome the C797S/T790M/activating-mutation (triple-mutation)-mediated EGFR–TKI resistance. In the present study, we identify brigatinib to be effective against triple-mutation-harbouring cells in vitro and in vivo. Our original computational simulation demonstrates that brigatinib fits into the ATP-binding pocket of triple-mutant EGFR. The structure–activity relationship analysis reveals the key component in brigatinib to inhibit the triple-mutant EGFR. The efficacy of brigatinib is enhanced markedly by combination with anti-EGFR antibody because of the decrease of surface and total EGFR expression. Thus, the combination therapy of brigatinib with anti-EGFR antibody is a powerful candidate to overcome triple-mutant EGFR.<br />EGFR変異陽性肺がんに対する新規耐性克服療法を発見 --今後予想されるオシメルチニブ耐性の克服へ--. 京都大学プレスリリース. 2017-04-03.
- Subjects :
- 0301 basic medicine
Lung Neoplasms
Cetuximab
Gene Expression
General Physics and Astronomy
Pharmacology
Piperazines
Mice
T790M
0302 clinical medicine
Carcinoma, Non-Small-Cell Lung
Antineoplastic Combined Chemotherapy Protocols
Osimertinib
Epidermal growth factor receptor
Aniline Compounds
Multidisciplinary
biology
Chemistry
Kinase
Panitumumab
Antibodies, Monoclonal
Tumor Burden
ErbB Receptors
030220 oncology & carcinogenesis
medicine.drug
Combination therapy
Brigatinib
Science
Mice, Nude
Antineoplastic Agents
Molecular Dynamics Simulation
Article
General Biochemistry, Genetics and Molecular Biology
03 medical and health sciences
Organophosphorus Compounds
In vivo
Cell Line, Tumor
medicine
Animals
Humans
Protein Kinase Inhibitors
Acrylamides
General Chemistry
Survival Analysis
Xenograft Model Antitumor Assays
respiratory tract diseases
Pyrimidines
030104 developmental biology
Drug Resistance, Neoplasm
Mutation
biology.protein
Subjects
Details
- Language :
- English
- ISSN :
- 20411723
- Volume :
- 8
- Issue :
- 1
- Database :
- OpenAIRE
- Journal :
- Nature Communications
- Accession number :
- edsair.doi.dedup.....a4f1dd6b5563fa2ad508d337f7273a95