Acquired BRAF V600E Mutation as Resistant Mechanism after Treatment with Osimertinib
Acquired BRAF V600E Mutation as Resistant Mechanism after Treatment with Osimertinib
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DOI：
10.1016/j.jtho.2016.11.2231
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发表时间：
2017-03-01
影响因子：
20.4
通讯作者：
Yang, James Chih-Hsin
中科院分区：
文献类型：
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作者：
Ho, Chao-Chi;Liao, Wei-Yu;Yang, James Chih-Hsin
介绍：AZD 9291（奥希替尼）设计用于使用第一代和第二代EGFR）酪氨酸激酶抑制剂后获得性T790 M突变。奥希替尼治疗后出现的一些耐药机制，包括新获得的EGFR C797 S突变，已被确定。目前还不清楚，但是，旁路途径是否也是一种机制，在奥希替尼treatment.Methods后，患者的阻力：恶性胸腔积液细胞收集和培养的时间与奥希替尼治疗的患者进展。通过基质辅助激光解吸电离-飞行时间质谱法进行肿瘤基因分型。测定EGFR、AKT、MEK和ERK磷酸化。锚定依赖性集落形成试验用于药物敏感性。结果：获得性突变，BRAF V600 E，被发现在进展的时间，而奥希替尼治疗的患者。从恶性胸腔积液生长的细胞是敏感的BRAF V600 E抑制剂，更容易受到联合治疗与osimertinib.Conclusions：一个潜在的机制，获得性耐药奥希替尼T790 M患者是通过BRAF途径。同时阻断BRAF和EGFR具有显著的抑制作用。(C)2016年国际肺癌研究协会。爱思唯尔公司出版All rights reserved.
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.