Resistance mechanisms to osimertinib in EGFR-mutated non-small cell lung cancer

Osimertinib is an irreversible, third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor that is highly selective for EGFR- activating mutations as well as the EGFR T790M mutation in patients with advanced non-small cell lung cancer (NSCLC) with EGFR oncogene addiction. Des...

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Veröffentlicht in:British journal of cancer Jg. 121; H. 9; S. 725 - 737
Hauptverfasser: Leonetti, Alessandro, Sharma, Sugandhi, Minari, Roberta, Perego, Paola, Giovannetti, Elisa, Tiseo, Marcello
Format: Journal Article
Sprache:Englisch
Veröffentlicht: London Nature Publishing Group UK 29.10.2019
Nature Publishing Group
Schlagworte:
1-Phosphatidylinositol 3-kinase
631/67/1059/2326
692/4028/67/1612/1350
Acrylamides - pharmacology
Acrylamides - therapeutic use
Addictions
Aniline Compounds - pharmacology
Aniline Compounds - therapeutic use
Biomedical and Life Sciences
Biomedicine
c-Met protein
Cancer Research
Carcinoma, Non-Small-Cell Lung - drug therapy
Carcinoma, Non-Small-Cell Lung - enzymology
Carcinoma, Non-Small-Cell Lung - genetics
Chemotherapy
Drug Resistance
Drug Resistance, Neoplasm
Enzyme inhibitors
Epidemiology
Epidermal growth factor
Epidermal growth factor receptors
ErbB Receptors - antagonists & inhibitors
ErbB Receptors - genetics
ErbB Receptors - metabolism
ErbB-2 protein
Genetic transformation
Genotyping
Humans
Kinases
Lung cancer
Lung Neoplasms - drug therapy
Lung Neoplasms - enzymology
Lung Neoplasms - genetics
MAP kinase
Molecular Medicine
Molecular modelling
Mutation
Non-small cell lung carcinoma
Oncology
Protein Kinase Inhibitors - pharmacology
Protein-tyrosine kinase
Randomized Controlled Trials as Topic
Review
Review Article
Signal transduction
Small cell lung carcinoma
Targeted cancer therapy
Tumors
ISSN:0007-0920, 1532-1827, 1532-1827
Online-Zugang:Volltext
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Zusammenfassung:Osimertinib is an irreversible, third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor that is highly selective for EGFR- activating mutations as well as the EGFR T790M mutation in patients with advanced non-small cell lung cancer (NSCLC) with EGFR oncogene addiction. Despite the documented efficacy of osimertinib in first- and second-line settings, patients inevitably develop resistance, with no further clear-cut therapeutic options to date other than chemotherapy and locally ablative therapy for selected individuals. On account of the high degree of tumour heterogeneity and adaptive cellular signalling pathways in NSCLC, the acquired osimertinib resistance is highly heterogeneous, encompassing EGFR - dependent as well as EGFR-independent mechanisms. Furthermore, data from repeat plasma genotyping analyses have highlighted differences in the frequency and preponderance of resistance mechanisms when osimertinib is administered in a front-line versus second-line setting, underlying the discrepancies in selection pressure and clonal evolution. This review summarises the molecular mechanisms of resistance to osimertinib in patients with advanced EGFR- mutated NSCLC, including MET/HER2 amplification, activation of the RAS–mitogen-activated protein kinase (MAPK) or RAS–phosphatidylinositol 3-kinase (PI3K) pathways, novel fusion events and histological/phenotypic transformation, as well as discussing the current evidence regarding potential new approaches to counteract osimertinib resistance.
Bibliographie:ObjectType-Article-1
SourceType-Scholarly Journals-1
ObjectType-Feature-2
content type line 14
ObjectType-Literature Review-3
ObjectType-Review-3
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ISSN:0007-0920
1532-1827
1532-1827
DOI:10.1038/s41416-019-0573-8