ID1 mediates resistance to osimertinib in EGFR T790M-positive non-small cell lung cancer through epithelial-mesenchymal transition

• Published in: BMC pulmonary medicine Vol. 21; no. 1; p. 163
• Main Authors: Liu, Kejun, Chen, Xianwen, Wu, Ligang, Chen, Shiyuan, Fang, Nianxin, Cai, Limin, Jia, Jun
• Format: Journal Article
• Language: English
• Published: England BioMed Central Ltd 15.05.2021; BioMed Central; BMC
• Subjects: Acrylamides - pharmacology; Aniline Compounds - pharmacology; Apoptosis; Cadherins - metabolism; Cancer therapies; Carcinoma, Non-Small-Cell Lung - drug therapy; Carcinoma, Non-Small-Cell Lung - genetics; Carcinoma, Non-Small-Cell Lung - pathology; Cell culture; Cell cycle; Cell differentiation; Cell growth; Cell Line, Tumor; Cell Proliferation; Chemotherapy; Drug resistance; Drug Resistance, Neoplasm; Drug therapy; E-cadherin; EGFR T790M; Epidermal growth factor receptors; Epithelial cells; Epithelial-Mesenchymal Transition - drug effects; Epithelial–mesenchymal transition (EMT); ErbB Receptors - genetics; Flow cytometry; Genetic aspects; Health aspects; Humans; ID1; Id1 protein; Inhibitor of Differentiation Protein 1 - genetics; Inhibitor of Differentiation Protein 1 - metabolism; Kinases; Lung cancer; Lung cancer, Non-small cell; Lung Neoplasms - drug therapy; Lung Neoplasms - genetics; Medical prognosis; Mesenchyme; mRNA; Mutation; Non-small cell lung carcinoma; Non-small-cell lung cancer (NSCLC); Osimertinib; Polymerase chain reaction; Protein Kinase Inhibitors - pharmacology; Protein-tyrosine kinase; Proteins; Pulmonology; Small cell lung carcinoma; Stem cells; Targeted cancer therapy; Transcription factors; Tumors; Vimentin; China; United States > US; Japan; Grand Island New York; Osimertinib; Epithelial–mesenchymal transition (EMT); Non-small-cell lung cancer (NSCLC); Drug resistance; EGFR T790M; ID1
• ISSN: 1471-2466; 1471-2466
• DOI: 10.1186/s12890-021-01540-4

ID1 is associated with resistance to the first generation of EGFR tyrosine kinase inhibitors (EGFR-TKIs) in non-small cell lung cancer (NSCLC). However, the effect of ID1 expression on osimertinib resistance in EGFR T790M-positive NSCLC is not clear. We established a drug-resistant cell line, H1975/OR, from the osimertinib-sensitive cell line H1975. Alterations in ID1 protein expression and Epithelial-mesenchymal transition (EMT)-related proteins were detected with western blot analysis. RT-PCR was used to evaluate the differences of gene mRNA levels. ID1 silencing and overexpression were used to investigate the effects of related gene on osimertinib resistance. Cell Counting Kit-8 (CCK8) was used to assess the proliferation rate in cells with altered of ID1 expression. Transwell assay was used to evaluate the invasion ability of different cells. The effects on the cell cycle and apoptosis were also compared using flow cytometry. In our study, we found that in osimertinib-resistant NSCLC cells, the expression level of the EMT-related protein E-cadherin was lower than that of sensitive cells, while the expression level of ID1 and vimentin were higher than those of sensitive cells. ID1 expression levels was closely related to E-cadherin and vimentin in both osimertinib-sensitive and resistant cells. Alteration of ID1 expression in H1975/OR cells could change the expression of E-cadherin. Downregulating ID1 expression in H1975/OR cells could inhibit cell proliferation, reduce cell invasion, promote cell apoptosis and arrested the cell cycle in the G1/G0 stage phase. Our study suggests that ID1 may induce EMT in EGFR T790M-positive NSCLC, which mediates drug resistance of osimertinib. Our study revealed the mechanism of ID1 mediated resistance to osimertinib in EGFR T790M-positive NSCLC through EMT, which may provide new ideas and methods for the treatment of EGFR mutated NSCLC after osimertinib resistance.