获得性 BRAF 重排诱导 EGFR 突变型肺癌对 EGFR 治疗的获得性耐药。
Acquired BRAF Rearrangements Induce Secondary Resistance to EGFR therapy in EGFR-Mutated Lung Cancers.
机构信息
Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York.
Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.
出版信息
J Thorac Oncol. 2019 May;14(5):802-815. doi: 10.1016/j.jtho.2018.12.038. Epub 2019 Mar 1.
INTRODUCTION
Multiple genetic mechanisms have been identified in EGFR-mutant lung cancers as mediators of acquired resistance (AR) to EGFR tyrosine kinase inhibitors (TKIs), but many cases still lack a known mechanism.
METHODS
To identify novel mechanisms of AR, we performed targeted large panel sequencing of samples from 374 consecutive patients with metastatic EGFR-mutant lung cancer, including 174 post-TKI samples, of which 38 also had a matched pre-TKI sample. Alterations hypothesized to confer AR were introduced into drug-sensitive EGFR-mutant lung cancer cell lines (H1975, HCC827, and PC9) by using clustered regularly interspaced short palindromic repeats/Cas9 genome editing. MSK-LX138cl, a cell line with EGFR exon 19 deletion (ex19del) and praja ring finger ubiquitin ligase 2 gene (PJA2)/BRAF fusion, was generated from an EGFR TKI-resistant patient sample.
RESULTS
We identified four patients (2.3%) with a BRAF fusion (three with acylglycerol kinase gene (AGK)/BRAF and one with PJA2/BRAF) in samples obtained at AR to EGFR TKI therapy (two posterlotinib samples and two posterlotinib and postosimertinib samples). Pre-TKI samples were available for two of four patients and both were negative for BRAF fusion. Induction of AGK/BRAF fusion in H1975 (L858R + T790M), PC9 (ex19del) and HCC827 (ex19del) cells increased phosphorylation of BRAF, MEK1/2, ERK1/2, and signal transducer and activator of transcription 3 and conferred resistance to growth inhibition by osimertinib. MEK inhibition with trametinib synergized with osimertinib to block growth. Alternately, a pan-RAF inhibitor as a single agent blocked growth of all cell lines with mutant EGFR and BRAF fusion.
CONCLUSION
BRAF fusion is a mechanism of AR to EGFR TKI therapy in approximately 2% of patients. Combined inhibition of EGFR and MEK (with osimertinib and trametinib) or BRAF (with a pan-RAF inhibitor) are potential therapeutic strategies that should be explored.
简介
已发现多种遗传机制可介导表皮生长因子受体（EGFR）突变型肺癌对 EGFR 酪氨酸激酶抑制剂（TKI）的获得性耐药（AR），但许多病例仍缺乏已知的机制。
方法
为了确定 AR 的新机制，我们对 374 例转移性 EGFR 突变型肺癌患者的样本进行了靶向大panel 测序，其中包括 174 例 TKI 后样本，其中 38 例还有匹配的 TKI 前样本。通过使用成簇规律间隔短回文重复序列/ Cas9 基因组编辑，将假设能赋予 AR 的改变引入到对 EGFR 敏感的突变型肺癌细胞系（H1975、HCC827 和 PC9）中。MSK-LX138cl 是一个具有 EGFR 外显子 19 缺失（ex19del）和 praja 指环指泛素连接酶 2 基因（PJA2）/ BRAF 融合的细胞系，由一名对 EGFR TKI 耐药的患者的样本生成。
结果
我们在 EGFR TKI 治疗后 AR 的 4 名患者（2.3%）的样本中发现了 4 例 BRAF 融合（3 例为酰基甘油激酶基因（AGK）/ BRAF，1 例为 PJA2/BRAF）（2 例为 postlotinib 样本，2 例为 postlotinib 和 postosimertinib 样本）。其中两名患者的 TKI 前样本可用，均为 BRAF 融合阴性。在 H1975（L858R + T790M）、PC9（ex19del）和 HCC827（ex19del）细胞中诱导 AGK/BRAF 融合增加了 BRAF、MEK1/2、ERK1/2 和信号转导和转录激活因子 3 的磷酸化，并对 osimertinib 抑制生长产生了耐药性。用 trametinib 抑制 MEK 与 osimertinib 协同阻断生长。相反，一种泛 RAF 抑制剂作为单一药物可阻断所有具有突变型 EGFR 和 BRAF 融合的细胞系的生长。
结论
BRAF 融合是约 2%的患者对 EGFR TKI 治疗产生 AR 的机制。联合抑制 EGFR 和 MEK（用 osimertinib 和 trametinib）或 BRAF（用泛 RAF 抑制剂）可能是值得探索的治疗策略。
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