Anlotinib can overcome acquired resistance to EGFR-TKIs via FGFR1 signaling in non-small cell lung cancer without harboring EGFR T790M mutation
Anlotinib can overcome acquired resistance to EGFR-TKIs via FGFR1 signaling in non-small cell lung cancer without harboring EGFR T790M mutation
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DOI：
10.1111/1759-7714.13485
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发表时间：
2020-05-20
期刊：
影响因子：
2.9
通讯作者：
Huang, Jian-an
中科院分区：
文献类型：
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作者：
Lian, Zengzhi;Du, Wenwen;Huang, Jian-an
背景尽管许多研究已经确定了对EGFR-TKIs耐药的机制，但获得性耐药仍然是EGFR-TKIs单药治疗的主要限制。EGFR T790 M突变在HiSeq 4000平台上测序。通过基于基因组分析仪的深度测序分析来自HCC 827和HCC 827吉非替尼耐药（GR）细胞的mRNA。采用流式细胞仪（fluorescence-activated cell sorting，FACS）检测安洛替尼对HCC 827 GR细胞凋亡及细胞周期阻滞的影响。结果在PC-9 GR细胞系中发现T790 M突变，而在HCC 827 GR细胞系中未发现T790 M突变。在体外和小鼠异种移植模型中，Anlotinib可通过抑制FGFR 1抑制HCC 827 GR细胞的生长。此外，FGFR 1在HCC 827 GR细胞中过表达，并且FGFR 1的敲低逆转了HCC 827 GR细胞中的吉非替尼耐药性。结论FGFR 1过表达可能是EGFR-TKI获得性耐药的机制之一，且Anlotinib可抑制无T790 M突变的EGFR-TKI耐药NSCLC细胞的生长。
Background Although many studies have defined mechanisms of resistance to EGFR-TKIs, acquired resistance remains the major limitation of monotherapy with EGFR-TKIs.Methods Cell viability was analyzed using a Cell Counting Kit-8 (CCK-8) assay. EGFR T790M mutation was sequenced on a HiSeq 4000 platform. mRNAs from HCC827 and HCC827 gefitinib-resistant (GR) cells were analyzed by genome analyzer-based deep sequencing. The effect of anlotinib on apoptosis and cell cycle arrest of HCC827 GR was detected by fluorescence-activated cell sorting (FACS) analysis. A mouse xenograft model was used to assess the effect of anlotinib on HCC827 GR cells.Results The T790M mutation was found in the PC-9 GR cell line but not in the HCC827 GR cell line. Anlotinib could suppress the growth of HCC827 GR cells by inhibiting FGFR1 in vitro and in a mouse xenograft model. Moreover, FGFR1 was overexpressed in HCC827 GR cells, and the knockdown of FGFR1 reversed gefitinib resistance in HCC827 GR cells. Furthermore, anlotinib induced apoptosis and cell cycle arrest in HCC827 GR cells by increasing the activity of Caspase-3.Conclusions FGFR1 overexpression could be the mechanism of EGFR-TKI acquired resistance and anlotinib can suppresse the growth of EGFR-TKI-resistant NSCLC cells without T790M mutation.