Single-Cell Analyses Reveal Diverse Mechanisms of Resistance to EGFR Tyrosine Kinase Inhibitors in Lung Cancer.
Single-Cell Analyses Reveal Diverse Mechanisms of Resistance to EGFR Tyrosine Kinase Inhibitors in Lung Cancer.
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单细胞分析揭示了肺癌对 EGFR 酪氨酸激酶抑制剂的多种耐药机制。
DOI：
10.1158/0008-5472.can-20-2811
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发表时间：
2021-09-15
期刊：
影响因子：
11.2
通讯作者：
Kobayashi SS
中科院分区：
文献类型：
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作者：
Kashima Y;Shibahara D;Suzuki A;Muto K;Kobayashi IS;Plotnick D;Udagawa H;Izumi H;Shibata Y;Tanaka K;Fujii M;Ohashi A;Seki M;Goto K;Tsuchihara K;Suzuki Y;Kobayashi SS
肿瘤异质性是携带表皮生长因子受体（EGFR）突变的肺癌对酪氨酸激酶抑制剂（TKI）耐药的基础。先前的证据表明，预先存在的耐药细胞的子集是通过EGFR-TKI治疗选择的，或者，不同的获得性耐药机制来自耐药持续（DTP）细胞。许多研究使用了大量的肿瘤标本或亚克隆耐药细胞系来鉴定耐药机制。然而，肿瘤内异质性可能导致对治疗的不同反应，需要额外的方法来揭示完整的耐药机制谱。使用EGFR-TKI耐药细胞模型和临床标本，我们进行了单细胞RNA-seq和单细胞ATAC-seq分析，以确定处于完全耐药状态的亲本细胞、DTP和肿瘤细胞的转录和表观遗传景观。除了已知可诱导EGFR-TKI耐药的AURKA、VIM和AXL外，CD74被鉴定为在耐药状态中起关键作用的新基因。体外和体内实验表明，CD74上调赋予对EGFR-TKI奥希替尼的抗性并阻断细胞凋亡，从而使肿瘤再生。总体而言，这项研究为EGFR-TKI耐药机制提供了新的见解。
Tumor heterogeneity underlies resistance to tyrosine kinase inhibitors (TKI) in lung cancers harboring epidermal growth factor receptor (EGFR) mutations. Previous evidence suggested that subsets of preexisting resistant cells are selected by EGFR-TKI treatment, or alternatively, that diverse acquired resistance mechanisms emerge from drug-tolerant persister (DTP) cells. Many studies have used bulk tumor specimens or subcloned resistant cell lines to identify resistance mechanism. However, intratumoral heterogeneity can result in divergent responses to therapies, requiring additional approaches to reveal the complete spectrum of resistance mechanisms. Using EGFR-TKI-resistant cell models and clinical specimens, we performed single-cell RNA-seq and single-cell ATAC-seq analyses to define the transcriptional and epigenetic landscape of parental cells, DTPs, and tumor cells in a fully resistant state. In addition to AURKA, VIM, and AXL, which are all known to induce EGFR-TKI resistance, CD74 was identified as a novel gene that plays a critical role in the drug-tolerant state. In vitro and in vivo experiments demonstrated that CD74 upregulation confers resistance to the EGFR-TKI osimertinib and blocks apoptosis, enabling tumor regrowth. Overall, this study provides new insight into the mechanisms underlying resistance to EGFR-TKIs.