miR-762 activation confers acquired resistance to gefitinib in non-small cell lung cancer

Epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) (e.g. gefitinib) currently remain the first-line treatment for patients with advanced non-small-cell lung cancer (NSCLC) with activating EGFR mutation. However, acquired resistance to gefitinib, which occurs frequently through...

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Published in:	BMC cancer Vol. 19; no. 1; p. 1203
Main Authors:	Ge, Peng, Cao, Lei, Chen, Xin, Jing, Ruijun, Yue, Wanxia
Format:	Journal Article
Language:	English
Published:	England BioMed Central Ltd 10-12-2019 BioMed Central BMC
Subjects:	ABR Afatinib Analysis Animals Apoptosis Biomarkers Carcinoma, Non-Small-Cell Lung - drug therapy Carcinoma, Non-Small-Cell Lung - genetics Carcinoma, Non-Small-Cell Lung - mortality Cell death Cell Line, Tumor Cell Survival Chemotherapy Cytokines DNA microarrays Drug Resistance, Neoplasm - genetics Enzyme-linked immunosorbent assay Epidermal growth factor Epidermal growth factor receptors ErbB Receptors - antagonists & inhibitors ErbB Receptors - genetics Female Gefitinib Gefitinib - therapeutic use Gefitinib resistance Gene Expression Regulation, Neoplastic - drug effects Genetic aspects GTPase-Activating Proteins - genetics Health aspects Humans IL-6 Interleukin 6 Interleukin-6 - genetics Interleukin-6 - metabolism Kinases Laboratory animals Luciferase Lung cancer Lung Neoplasms - drug therapy Lung Neoplasms - genetics Lung Neoplasms - mortality Male Mergers, acquisitions and divestments Mice Mice, Inbred BALB C Mice, Nude MicroRNA MicroRNAs MicroRNAs - genetics Middle Aged miR-762 miRNA Mutagenesis Mutation Non-small cell lung carcinoma Non-small-cell lung cancer (NSCLC) Pathogenesis Phenols (Class of compounds) Post-transcription Protein Kinase Inhibitors - therapeutic use Protein-tyrosine kinase Proteins Recurrence (Disease) Scientific equipment industry Signal Transduction - drug effects Site-directed mutagenesis Small cell lung cancer Small cell lung carcinoma Targeted cancer therapy Tyrosine Xenograft Model Antitumor Assays Xenografts United States China Beijing China United States > US miR-762 ABR Non-small-cell lung cancer (NSCLC) IL-6 Gefitinib resistance
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Summary:	Epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) (e.g. gefitinib) currently remain the first-line treatment for patients with advanced non-small-cell lung cancer (NSCLC) with activating EGFR mutation. However, acquired resistance to gefitinib, which occurs frequently through unidentified mechanisms, significantly attenuate therapeutic effectiveness. Previous miRNA microarray analysis reveals that expression levels of a conserved oncomiR miR-762 are significantly upregulated in gefitinib-resistant NSCLC cells. We therefore aim to elucidate the role and underlying mechanisms of miR-762 during the pathogenesis of gefitinib resistance. miR-762 expression in gefitinib-resistant NSCLC tissues and cells was evaluated using RT-qPCR. The potential regulation of miR-762 expression by IL-6 was studied using pharmacological and biochemical approaches. Effects of miR-762 manipulation on sensitivity to gefitinib was assessed using MTT, apoptotic ELISA and xenograft model. Finally, the posttranscriptional regulation of active BCR related protein (ABR) by miR-762 was determined using luciferase assay and site-directed mutagenesis. miR-762 expression was upregulated in gefitinib-resistant NSCLC tissues and cells, and this upregulation predicted a poor post-chemotherapy prognosis in NSCLC patients. miR-762 upregulation, induced by IL-6 signaling, significantly enhanced cell survival and rendered NSCLC cells unresponsiveness to gefitinib-elicited cell death. We finally provided the evidence that the oncogenic effect of miR-762 was mediated mainly through posttranscriptional repression of ABR in gefitinib-resistant NSCLC cells. Our findings provide a rationale for future efforts testing miR-762 inhibition and ABR restoration co-treatment in patients with recurrent EGFR mutant NSCLC to therapeutically combat the heterogeneity of EGFR-TKIs resistance mechanisms.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	1471-2407 1471-2407
DOI:	10.1186/s12885-019-6416-4