癌症研究
奥西默替尼
生物
下调和上调
肺癌
表皮生长因子受体
酪氨酸激酶
癌症
抗药性
表观遗传学
医学
信号转导
埃罗替尼
细胞生物学
基因
遗传学
病理
作者
Yukie Kashima,Daisuke Shibahara,Ayako Suzuki,Kyoko Muto,I Kobayashi,David Plotnick,Hibiki Udagawa,Hiroki Izumi,Yuji Shibata,Kosuke Tanaka,Masanori Fujii,Akihiro Ohashi,Masahide Seki,Kōichi Goto,Katsuya Tsuchihara,Yutaka Suzuki,Susumu Kobayashi
出处
期刊:Cancer Research
[American Association for Cancer Research]
日期:2021-07-09
卷期号:81 (18): 4835-4848
被引量:31
标识
DOI:10.1158/0008-5472.can-20-2811
摘要
Tumor heterogeneity underlies resistance to tyrosine kinase inhibitors (TKI) in lung cancers harboring 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. SIGNIFICANCE: Single-cell analyses identify diverse mechanisms of resistance as well as the state of tolerant cells that give rise to resistance to EGFR tyrosine kinase inhibitors.
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