Intercellular transfer of exosomal wild type EGFR triggers osimertinib resistance in non-small cell lung cancer.
Intercellular transfer of exosomal wild type EGFR triggers osimertinib resistance in non-small cell lung cancer.
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外泌体野生型 EGFR 的细胞间转移引发非小细胞肺癌奥希替尼耐药
DOI：
10.1186/s12943-021-01307-9
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发表时间：
2021-01-18
期刊：
影响因子：
37.3
通讯作者：
Fu L
中科院分区：
文献类型：
--
作者：
Wu S;Luo M;To KKW;Zhang J;Su C;Zhang H;An S;Wang F;Chen D;Fu L
背景表皮生长因子受体（EGFR）突变型肺癌是非小细胞肺癌（NSCLC）的一个主要亚群，奥希替尼是其一线治疗药物。然而，大多数接受奥希替尼治疗的患者最终在一年内复发。奥希替尼耐药的潜在机制仍然在很大程度上unexplored.MethodsExosomes分离进行差速离心。共培养实验通过细胞活力和凋亡实验来探讨药物敏感性的改变。进行免疫荧光和流式细胞术以可视化外泌体的形成或吸收。通过纳米颗粒跟踪分析或ELISA测量外来体分泌。建立了小鼠异种移植瘤模型，以评估外泌体对奥希替尼体内敏感性的影响。结果外泌体野生型EGFR蛋白的细胞间转移使奥希替尼在体外和体内对EGFR突变敏感的癌细胞产生耐药性。EGFR突变敏感细胞和EGFR非突变耐药细胞的共培养促进了EGFR突变癌细胞中的奥希替尼耐药表型，而从条件培养基中去除外泌体或通过中和抗体阻断外泌体EGFR减轻了这种表型。从机制上讲，奥希替尼通过上调Rab GT3（RAB 17）促进外泌体的释放。RAB 17的敲低导致外泌体分泌减少。此外，EGFR突变的癌细胞可以通过网格蛋白依赖的内吞作用将外泌体内化，然后外泌体野生型EGFR蛋白激活下游PI 3 K/AKT和MAPK信号通路并触发奥希替尼耐药。这可能代表了奥希替尼的一种新的耐药机制，并为靶向外泌体以预防和逆转奥希替尼耐药提供了概念验证。
BackgroundEpidermal growth factor receptor (EGFR)-mutated lung cancer constitutes a major subgroup of non-small cell lung cancer (NSCLC) and osimertinib is administrated as first-line treatment. However, most patients with osimertinib treatment eventually relapse within one year. The underlying mechanisms of osimertinib resistance remain largely unexplored.MethodsExosomes isolation was performed by differential centrifugation. Co-culture assays were conducted to explore the alteration of drug sensitivity by cell viability and apoptosis assays. Immunofluorescence and flow cytometry were performed to visualize the formation or absorption of exosomes. Exosomes secretion was measured by Nanoparticle Tracking Analysis or ELISA. The xenograft tumor model in mice was established to evaluate the effect of exosomes on osimertinib sensitivity in vivo.ResultsIntercellular transfer of exosomal wild type EGFR protein confers osimertinib resistance to EGFR-mutated sensitive cancer cells in vitro and in vivo. Co-culture of EGFR-mutated sensitive cells and EGFR-nonmutated resistant cells promoted osimertinib resistance phenotype in EGFR-mutated cancer cells, while depletion of exosomes from conditioned medium or blockade of exosomal EGFR by neutralizing antibody alleviated this phenotype. Mechanistically, osimertinib promoted the release of exosomes by upregulated a Rab GTPase (RAB17). Knockdown of RAB17 resulted in the decrease of exosomes secretion. Moreover, exosomes could be internalized by EGFR-mutated cancer cells via Clathrin-dependent endocytosis and then the encapsulated exosomal wild type EGFR protein activated downstream PI3K/AKT and MAPK signaling pathways and triggered osimertinib resistance.ConclusionsIntercellular transfer of exosomal wild type EGFR promotes osimertinib resistance in NSCLC, which may represent a novel resistant mechanism of osimertinib and provide a proof of concept for targeting exosomes to prevent and reverse the osimertinib resistance.
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DOI：
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发表时间：
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期刊：
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影响因子：
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作者：
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影响因子：
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2017-10-01
期刊：
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作者：
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DOI：
10.1097/jto.0000000000000033
发表时间：
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期刊：
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