Acquired BRAF G469A Mutation as a Resistance Mechanism to First-Line Osimertinib Treatment in NSCLC Cell Lines Harboring an EGFR Exon 19 Deletion

Background Osimertinib is a new third-generation, epidermal growth factor receptor-tyrosine kinase inhibitor highly selective for the epidermal growth factor receptor with both activating and T790M mutations. A recent phase III trial showed a statistically significant progression-free survival benef...

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Published in:Targeted oncology 2019-10, Vol.14 (5), p.619-626
Main Authors: La Monica, Silvia, Minari, Roberta, Cretella, Daniele, Bonelli, Mara, Fumarola, Claudia, Cavazzoni, Andrea, Galetti, Maricla, Digiacomo, Graziana, Riccardi, Federica, Petronini, Pier Giorgio, Tiseo, Marcello, Alfieri, Roberta
Format: Article
Language:English
Subjects:
Acrylamides - therapeutic use
Aniline Compounds - therapeutic use
Antineoplastic Agents - therapeutic use
Apoptosis
Biomedicine
Cancer therapies
Carcinoma, Non-Small-Cell Lung - drug therapy
Cell adhesion & migration
Cell culture
Cell growth
Cell Line, Tumor
Cell Proliferation
Cloning
Drug Resistance, Neoplasm - genetics
Epidermal growth factor
ErbB Receptors - genetics
Exons - genetics
Genotype
High-Throughput Nucleotide Sequencing
Humans
Kinases
Lung cancer
Lung Neoplasms - drug therapy
Medicine
Medicine & Public Health
Mutation
Oncology
Proto-Oncogene Proteins B-raf - genetics
Sequence Deletion - genetics
Short Communication
Targeted cancer therapy
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Summary:Background Osimertinib is a new third-generation, epidermal growth factor receptor-tyrosine kinase inhibitor highly selective for the epidermal growth factor receptor with both activating and T790M mutations. A recent phase III trial showed a statistically significant progression-free survival benefit with osimertinib vs. gefitinib or erlotinib as first-line treatment for EGFR -mutated non-small cell lung cancer, and preliminary data are available on resistance mechanisms to first-line osimertinib therapy. Objective The objective of this study was to examine potential in vitro mechanisms of acquired resistance to osimertinib in a cell model carrying an EGFR exon 19 deletion. Methods PC9 cells were cultured in the presence of increasing concentrations of osimertinib (ranging from 10 to 500 nM) to generate resistant cells. Three clones resistant to osimertinib (half maximal inhibitory concentration > 1 μM) were isolated, genotyped by next-generation sequencing and tested for drug sensitivity. Cell proliferation and migration, cell death, and signaling transduction pathways were analyzed. Results Our study revealed that all the three resistant clones developed acquired resistance via the BRAF G469A mutation maintaining a constitutive activation of the ERK pathway. Stable transfection of PC9 and HCC827 cells with a plasmid containing BRAF G469A rendered the cells resistant to osimertinib. Treatment with selumetinib and trametinib, but not dabrafenib, restored the sensitivity to osimertinib and enhanced cell death in the resistant clones with the BRAF G469A mutation. Conclusions Our in vitro studies revealed the BRAF G469A-activating mutation as a potential mechanism of acquired resistance to first-line osimertinib treatment, and provide a strategy of intervention to overcome this mechanism of resistance.
ISSN:1776-2596
1776-260X
DOI:10.1007/s11523-019-00669-x