Activation of AXL as a Preclinical Acquired Resistance Mechanism Against Osimertinib Treatment in EGFR-Mutant Non-Small Cell Lung Cancer Cells
Activation of AXL as a Preclinical Acquired Resistance Mechanism Against Osimertinib Treatment in EGFR-Mutant Non-Small Cell Lung Cancer Cells
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DOI：
10.1158/1541-7786.mcr-18-0628
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发表时间：
2019-02-01
影响因子：
5.2
通讯作者：
Toyooka, Shinichi
中科院分区：
文献类型：
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作者：
Namba, Kei;Shien, Kazuhiko;Toyooka, Shinichi
Osimertinib(AZD9291)对EGFR突变的晚期非小细胞肺癌(NSCLC)患者的一线治疗效果优于标准EGFR酪氨酸激酶抑制剂。然而，接受奥西美替尼治疗的患者最终会获得耐药性，需要新的治疗策略来克服获得性耐药性。在临床或临床前模型中，奥西美替尼获得性耐药的几种机制已被阐明。然而，当osimertinib最初用于EGFR突变的NSCLC时，其获得性耐药机制仍不清楚。在这项研究中，我们从EGFR突变的NSCLC细胞系中实验建立了获得的奥西美替尼耐药细胞系，并研究了耐药细胞的分子图谱，以揭示获得性耐药的机制。鉴定了不同的抗性机制，包括获得MET扩增、EMT诱导和Ax1上调。使用具有多基因面板的定向下一代测序，在我们的耐药细胞系中没有检测到二次突变。在三个MET扩增的细胞系中，有一个细胞系对奥西美替尼和克里佐替尼的组合敏感。携带T790M突变的H1975细胞株的获得性耐药细胞株AXL表达上调，奥西美替尼和卡波赞替尼(一种包括AXL在内的多种酪氨酸激酶的抑制剂)在体外和体内均可抑制这些细胞株的生长。我们的结果提示AXL可能是克服奥西莫替尼获得性耐药的治疗靶点。意义：AXL上调是奥西梅替尼获得性耐药的机制之一，奥西梅替尼和库赞替尼的联合应用可能是克服奥西莫替尼耐药的关键治疗方法。
Osimertinib (AZD9291) has an efficacy superior to that of standard EGFR-tyrosine kinase inhibitors for the first-line treatment of patients with EGFR-mutant advanced non-small cell lung cancer (NSCLC). However, patients treated with osimertinib eventually acquire drug resistance, and novel therapeutic strategies to overcome acquired resistance are needed. In clinical or preclinical models, several mechanisms of acquired resistance to osimertinib have been elucidated. However, the acquired resistance mechanisms when osimertinib is initially used for EGFR-mutant NSCLC remain unclear. In this study, we experimentally established acquired osimertinib-resistant cell lines from EGFR-mutant NSCLC cell lines and investigated the molecular profiles of resistant cells to uncover the mechanisms of acquired resistance. Various resistance mechanisms were identified, including the acquisition of MET amplification, EMT induction, and the upregulation of AXL. Using targeted next-generation sequencing with a multigene panel, no secondary mutations were detected in our resistant cell lines. Among three MET-amplified cell lines, one cell line was sensitive to a combination of osimertinib and crizotinib. Acquired resistance cell lines derived from H1975 harboring the T790M mutation showed AXL upregulation, and the cell growth of these cell lines was suppressed by a combination of osimertinib and cabozantinib, an inhibitor of multiple tyrosine kinases including AXL, both in vitro and in vivo. Our results suggest that AXL might be a therapeutic target for overcoming acquired resistance to osimertinib.Implications: Upregulation of AXL is one of the mechanisms of acquired resistance to osimertinib, and combination of osimertinib and cabozantinib might be a key treatment for overcoming osimertinib resistance.