Comprehensive analysis of circular RNA profiling in AZD9291‐resistant non‐small cell lung cancer cell lines

Abstract

Background Osimertinib (AZD9291), a third‐generation EGFR‐tyrosine kinase inhibitor, can effectively prolong survival in non‐small cell lung cancer (NSCLC) patients with EGFR mutations, particularly T790M mutations; however, acquired resistance to AZD9291 is inevitable, thus exploration of the targets of resistance is urgent. Methods Considering the important role of circular RNAs (circRNAs) in cancers, we established AZD9291‐resistant NSCLC cell lines (H1975/AZDR and HCC827/AZDR) and used microarray analysis to determine the circRNA expression profiles of the cells. The H1975/AZDR and HCC827/AZDR cell lines were induced by gradually increasing the drug concentration. CircRNA microarray expression profiles were obtained from H1975, HCC827, H1975/AZDR, and HCC827/AZDR cells and validated by quantitative reverse transcription PCR. Expression data were analyzed bioinformatically. Results The H1975/AZDR and HCC827/AZDR cell lines were successfully established. The half‐maximal inhibitory concentration and the invasion ability of H1975/AZDR and HCC827/AZDR cells were significantly enhanced. The proliferation rates of H1975/AZDR and HCC827/AZDR were much lower than H1975 and HCC827. Microarray analysis identified 15 504 circRNAs differentially expressed in H1975, HCC827, H1975/AZDR, and HCC827/AZDR cells. Among them, 7966 were upregulated and 7538 were downregulated more than two‐fold. We predicted the possible miRNAs of the top dysregulated circRNAs. Furthermore, Kyoto Encyclopedia of Genes and Genomes pathway analysis showed that the most modulated circRNAs regulate several cancers and cancer‐related pathways. Conclusion Our results reveal that circRNAs may play a role in NSCLC AZD9291 resistance and might be a promising molecular target candidate for gene therapy.

Keywords

• AZD9291
• circular RNA
• microarray
• NSCLC
• resistance