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Acquired BRAF V600E Mutation as Resistant Mechanism after Treatment with Osimertinib
Chao-Chi Ho1, Wei-Yu Liao1, Chih-An Lin2
1Department of Internal Medicine, National Taiwan University Hospital, National Taiwan University College of Medicine, Taipei, Republic of China.
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.
Insights
A BRAF V600E mutation caused osimertinib resistance in a patient with EGFR T790M. Combination therapy targeting BRAF and EGFR showed significant efficacy, suggesting BRAF pathway involvement in osimertinib resistance.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Osimertinib (AZD9291) is a third-generation EGFR tyrosine kinase inhibitor used for acquired T790M mutations.
- Mechanisms of resistance to osimertinib, such as EGFR C797S mutations, are known.
- Bypass pathway resistance after osimertinib treatment remains incompletely understood.
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