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IGF1R缺失促进MET扩增，作为HCC827非小细胞肺癌细胞对厄洛替尼获得性耐药的机制。

IGF1R depletion facilitates MET-amplification as mechanism of acquired resistance to erlotinib in HCC827 NSCLC cells.

作者信息

Hussmann Dianna, Madsen Anne Tranberg, Jakobsen Kristine Raaby, Luo Yonglun, Sorensen Boe Sandahl, Nielsen Anders Lade

机构信息

Department of Biomedicine, Aarhus University, Aarhus, Denmark.

Department of Clinical Biochemistry, Aarhus University Hospital, Aarhus, Denmark.

出版信息

Oncotarget. 2017 May 16;8(20):33300-33315. doi: 10.18632/oncotarget.16350.

DOI:10.18632/oncotarget.16350
PMID:28418902
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC5464869/
Abstract

EGFR-mutated non-small cell lung cancer patients experience relapse within 1-2 years of treatment with EGFR-inhibitors, such as erlotinib. Multiple resistance mechanisms have been identified including secondary EGFR-mutations, MET-amplification, and epithelial-mesenchymal transition (EMT). Previous studies have indicated a role of Insulin-like growth factor 1 receptor (IGF1R) in acquired resistance to EGFR-directed drugs as well as in EMT. In the present study, we have investigated the involvement of IGF1R in acquired high-dose erlotinib resistance in the EGFR-mutated lung adenocarcinoma cell line HCC827. We observed that IGF1R was upregulated in the immediate response to erlotinib and hyperactivated in erlotinib resistant HCC827 cells. Resistant cells additionally acquired features of EMT, whereas MET-amplification and secondary EGFR-mutations were absent. Using CRISPR/Cas9, we generated a HCC827(IGFR1-/-) cell line and subsequently investigated resistance development in response to high-dose erlotinib. Interestingly, HCC827(IGFR1-/-) cells were now observed to specifically amplify the MET gene. Additionally, we observed a reduced level of mesenchymal markers in HCC827(IGFR1-/-) indicating an intrinsic enhanced epithelial signature compared to HCC827 cells. In conclusion, our data show that IGF1R have an important role in defining selected resistance mechanisms in response to high doses of erlotinib.

摘要

表皮生长因子受体（EGFR）突变的非小细胞肺癌患者在使用EGFR抑制剂（如厄洛替尼）治疗后的1 - 2年内会出现复发。已确定多种耐药机制，包括继发性EGFR突变、MET扩增和上皮 - 间质转化（EMT）。先前的研究表明胰岛素样生长因子1受体（IGF1R）在对EGFR靶向药物的获得性耐药以及EMT过程中发挥作用。在本研究中，我们调查了IGF1R在EGFR突变的肺腺癌细胞系HCC827对高剂量厄洛替尼获得性耐药中的作用。我们观察到，在对厄洛替尼的即时反应中IGF1R上调，并且在对厄洛替尼耐药的HCC827细胞中过度激活。耐药细胞还获得了EMT特征，而不存在MET扩增和继发性EGFR突变。使用CRISPR/Cas9，我们构建了HCC827(IGFR1-/-)细胞系，随后研究了其对高剂量厄洛替尼的耐药发展情况。有趣的是，现在观察到HCC827(IGFR1-/-)细胞特异性扩增了MET基因。此外，我们观察到HCC827(IGFR1-/-)中间质标志物水平降低，表明与HCC827细胞相比其内在上皮特征增强。总之，我们的数据表明IGF1R在确定对高剂量厄洛替尼的特定耐药机制中起重要作用。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c4ac/5464869/e980ee6f2d24/oncotarget-08-33300-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c4ac/5464869/e26d85021a93/oncotarget-08-33300-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c4ac/5464869/a4892e068662/oncotarget-08-33300-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c4ac/5464869/9eccb5007b6b/oncotarget-08-33300-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c4ac/5464869/d9dda27aac6f/oncotarget-08-33300-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c4ac/5464869/1c6f3181cc8a/oncotarget-08-33300-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c4ac/5464869/529aec6d2b66/oncotarget-08-33300-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c4ac/5464869/e980ee6f2d24/oncotarget-08-33300-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c4ac/5464869/e26d85021a93/oncotarget-08-33300-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c4ac/5464869/a4892e068662/oncotarget-08-33300-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c4ac/5464869/9eccb5007b6b/oncotarget-08-33300-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c4ac/5464869/d9dda27aac6f/oncotarget-08-33300-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c4ac/5464869/1c6f3181cc8a/oncotarget-08-33300-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c4ac/5464869/529aec6d2b66/oncotarget-08-33300-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c4ac/5464869/e980ee6f2d24/oncotarget-08-33300-g007.jpg

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