Journal
JOURNAL OF THORACIC ONCOLOGY
Volume 12, Issue 3, Pages 567-572Publisher
ELSEVIER SCIENCE INC
DOI: 10.1016/j.jtho.2016.11.2231
Keywords
NSCLC; T790M; BRAF V600E; Acquired resistance; Targeted therapy
Categories
Funding
- National Taiwan University Hospital [NTUH 105-002996]
- Ministry of Science and Technology Taiwan [MOST103-2321-B-002-079, MOST 104-2321-B-002-072]
- Novartis [LGX818]
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Introduction: AZD9291 (osimertinib) is designed for acquired T790M mutation after first- and second generation EGFR) tyrosine kinase inhibitors have been used. Some of the resistance mechanisms that present after osimertinib treatment, including a newly acquired EGFR C797S mutation, have been identified. It is unclear, however, whether the bypass pathway is also a mechanism of resistance in patients after osimertinib treatment. Methods: Cells from malignant pleural effusion were collected and cultured at the time of progression in a patient being treated with osimertinib. Tumor genotyping was done by matrix-assisted laser desorption ionization-time of flight mass spectrometry. EGFR, AKT, MEK, and ERK phosphorylation were determined. An anchorage-dependent colony formation assay was used for drug sensitivity. Results: An acquired mutation, BRAF V600E, was found in the patient at the time of progression while being treated with osimertinib. Cells grown from malignant pleural effusion were sensitive to BRAF V600E inhibitor and were more vulnerable to a combination treatment with osimertinib. Conclusions: A potential mechanism of acquired resistance to osimertinib in patients with T790M is through the BRAF pathway. Simultaneous blockade of the BRAF and EGFR had a significant inhibitory effect. (C) 2016 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.
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