一组新的EGFR酪氨酸激酶抑制剂适应的非小细胞肺癌细胞系的表型可塑性。

IF 2.8 4区 生物学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY
Tharsagini V Nanthaprakash, Campbell W Gourlay, Ina Oehme, Michelle D Garrett, Jindrich Cinatl, Mark N Wass, Martin Michaelis
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引用次数: 0

摘要

本研究介绍了EGFR突变的非小细胞肺癌(NSCLC)细胞系HCC827和HCC4006适应EGFR激酶抑制剂吉非替尼(HCC827rGEFI2μm, HCC4006rGEFI1μm)、厄洛替尼(HCC827rERLO2μm, HCC4006rERLO1μm)和阿法替尼(HCC827rAFA50nm, HCC4006rAFA100nm)的新亚系。所有亚组均对吉非替尼、厄洛替尼、阿法替尼和第三代EGFR激酶抑制剂奥西替尼(osimertinib)耐药,后者克服了t790m介导的耐药。HCC4006rERLO1μm呈现纺锤样形态,这与之前在其前体细胞HCC4006rERLO0.5μm中检测到上皮间质转化(EMT)的结果一致。在HCC4006rGEFI1μm前体细胞系HCC4006rGEFI0.5μm和HCC4006rAFA100nm中也有EMT的报道,但HCC4006rGEFI1μm和HCC4006rAFA100nm的形态学不支持这一点,这表明在药物适应过程和已建立的耐药细胞系中,EMT调控具有可塑性。因此,与前体HCC4006rERLO0.5μm相比,HCC4006rERLO1μm表现出对MEK和AKT抑制剂的抗性。我们还在HCC4006和HCC827rGEFI2μm中检测到代谢可塑性,即暂时性的Warburg代谢。对细胞毒性抗癌药物,激酶抑制剂和HDAC抑制剂的反应谱导致每个亚线特异性的复杂模式,表明个体耐药表型。所有耐药亚型对至少一种研究药物保持敏感或表现出间接敏感。总之,EGFR激酶耐药的NSCLC亚系与其前体细胞的比较和代谢研究表明,在抗性形成过程和已建立的细胞系中,表型具有可塑性。这种可塑性可能有助于在不同实验室和实验室内实验中观察到的细胞系表型的众所周知的变异性。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Phenotypic plasticity in a novel set of EGFR tyrosine kinase inhibitor-adapted non-small cell lung cancer cell lines.

Here, we introduce novel sublines of the EGFR-mutant non-small cell lung cancer (NSCLC) cell lines HCC827 and HCC4006 adapted to the EGFR kinase inhibitors gefitinib (HCC827rGEFI2μm, HCC4006rGEFI1μm), erlotinib (HCC827rERLO2μm, HCC4006rERLO1μm) and afatinib (HCC827rAFA50nm, HCC4006rAFA100nm). All sublines displayed resistance to gefitinib, erlotinib, afatinib and the third-generation EGFR kinase inhibitor osimertinib that overcomes T790M-mediated resistance. HCC4006rERLO1μm displayed a spindle-like morphology in agreement with previous findings that had detected epithelial-mesenchymal transition (EMT) in its precursor cell line HCC4006rERLO0.5μm. EMT had also been reported for the HCC4006rGEFI1μm precursor cell line HCC4006rGEFI0.5μm and for HCC4006rAFA100nm, but the morphologies of HCC4006rGEFI1μm or HCC4006rAFA100nm did not support this, suggesting plasticity in EMT regulation during the drug adaptation process and in established resistant cell lines. Accordingly, HCC4006rERLO1μm displayed resistance to MEK and AKT inhibitors in contrast to its precursor HCC4006rERLO0.5μm. We also detected metabolic plasticity, that is a temporary Warburg metabolism, in HCC4006 and HCC827rGEFI2μm. Response profiles to cytotoxic anticancer drugs, kinase inhibitors and HDAC inhibitors resulted in complex patterns that were specific for each individual subline, indicating individual resistance phenotypes. All resistant sublines remained sensitive or displayed collateral sensitivity to at least one of the investigated drugs. In conclusion, the comparison of EGFR kinase-resistant NSCLC sublines with their precursor cell lines that had been previously characterised at a lower resistance level and metabolic investigations indicated phenotypic plasticity during the resistance formation process and in established cell lines. This plasticity may contribute to the well-known variability in cell line phenotypes observed between different laboratories and in intra-laboratory experiments.

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来源期刊
FEBS Open Bio
FEBS Open Bio BIOCHEMISTRY & MOLECULAR BIOLOGY-
CiteScore
5.10
自引率
0.00%
发文量
173
审稿时长
10 weeks
期刊介绍: FEBS Open Bio is an online-only open access journal for the rapid publication of research articles in molecular and cellular life sciences in both health and disease. The journal''s peer review process focuses on the technical soundness of papers, leaving the assessment of their impact and importance to the scientific community. FEBS Open Bio is owned by the Federation of European Biochemical Societies (FEBS), a not-for-profit organization, and is published on behalf of FEBS by FEBS Press and Wiley. Any income from the journal will be used to support scientists through fellowships, courses, travel grants, prizes and other FEBS initiatives.
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