Epithelial-to-mesenchymal transition is a resistance mechanism to sequential MET-TKI treatment of MET-amplified EGFR-TKI resistant non-small cell lung cancer cells.
Epithelial-to-mesenchymal transition is a resistance mechanism to sequential MET-TKI treatment of MET-amplified EGFR-TKI resistant non-small cell lung cancer cells.
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DOI：
10.21037/tlcr-20-522
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发表时间：
2020-10
影响因子：
4
通讯作者：
Sorensen BS
中科院分区：
文献类型：
--
作者：
Clement MS;Gammelgaard KR;Nielsen AL;Sorensen BS
酪氨酸激酶抑制剂（TKI）耐药是治疗非小细胞肺癌（NSCLC）的主要障碍。MET扩增导致5-20%的初始敏感突变NSCLC患者对EGFR-TKIs产生耐药性，而EGFR-TKIs和MET- tkis联合治疗可以克服这种耐药性。然而，MET-TKI耐药性也不可避免地会出现。因此，了解这种序贯耐药的发展对于确定下一步治疗的适当步骤非常重要。为了研究MET-TKI治疗的序贯耐药，我们在MET扩增介导厄洛替尼耐药的egfr突变HCC827细胞中建立了两步TKI耐药模型。随后用增加剂量的MET-TKIs卡马替尼或克唑替尼联合厄洛替尼治疗这些细胞以建立耐药性。在所有MET-TKI耐药细胞系中，我们系统地观察到上皮到间质转化（EMT），明显表现为E-cadherin表达降低，vimentin和ZEB1表达增加。此外，在所有MET-TKI耐药细胞系中，FGFR1表达增加，6个耐药细胞系中有4个对FGFR抑制的敏感性增加，表明FGFR1介导的旁路信号传导。EMT在NSCLC细胞中发生EGFR-TKI和MET-TKI耐药的过程中很常见。我们的发现有助于证明EMT是一种常见的TKI耐药机制。
Tyrosine kinase inhibitor (TKI) resistance is a major obstacle in treatment of non-small cell lung cancer (NSCLC). MET amplification drives resistance to EGFR-TKIs in 5–20% of initially sensitive mutated NSCLC patients, and combined treatment with EGFR-TKIs and MET-TKIs can overcome this resistance. Yet, inevitably MET-TKI resistance will also occur. Hence, knowledge on development of this sequential resistance is important for identifying the proper next step in treatment. To investigate sequential resistance to MET-TKI treatment, we established a two-step TKI resistance model in EGFR-mutated HCC827 cells with MET amplification-mediated erlotinib resistance. These cells were subsequently treated with increasing doses of the MET-TKIs capmatinib or crizotinib in combination with erlotinib to establish resistance. In all the MET-TKI resistant cell lines, we systematically observed epithelial-to-mesenchymal transition (EMT) evident by decreased expression of E-cadherin and increased expression of vimentin and ZEB1. Furthermore, FGFR1 expression was increased in all MET-TKI resistant cell lines and four out of the six resistant cell lines had increased sensitivity to FGFR inhibition, indicating FGFR1-mediated bypass signaling. EMT is common in the development of sequential EGFR-TKI and MET-TKI resistance in NSCLC cells. Our findings contribute to the evidence of EMT as a common TKI resistance mechanism.