Abstract
BackgroundID1 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.MethodsWe 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.ResultsIn 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.ConclusionsOur 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.
Highlights
ID1 is associated with resistance to the first generation of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (EGFR-Tyrosine kinase inhibitors (TKIs)) in non-small cell lung cancer (NSCLC)
For patients with advanced NSCLC harboring epidermal growth factor receptor (EGFR) gene mutations, which accounts for 30–50% of NSCLC cases in East Asia, the first generation of EGFR tyrosine kinase inhibitors (EGFR-TKIs) such as gefitinib and erlotinib have superior therapeutic efficacy compared to traditional platinum-based chemotherapy [3, 4] and the median progression-free survival (PFS) is 9–13 months
Our study indicated that overexpression of ID1 could induce Epithelial–mesenchymal transition (EMT) in EGFR T790M-positive NSCLC cells, which may mediate drug resistance to osimertinib
Summary
ID1 is associated with resistance to the first generation of EGFR tyrosine kinase inhibitors (EGFR-TKIs) in non-small cell lung cancer (NSCLC). For patients with advanced NSCLC harboring epidermal growth factor receptor (EGFR) gene mutations, which accounts for 30–50% of NSCLC cases in East Asia, the first generation of EGFR tyrosine kinase inhibitors (EGFR-TKIs) such as gefitinib and erlotinib have superior therapeutic efficacy compared to traditional platinum-based chemotherapy [3, 4] and the median progression-free survival (PFS) is 9–13 months. These patients will eventually suffered secondary drug resistance during the targeted therapy and most of them may harbor the T790M mutation in exon 20 of the EGFR gene [5].
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