Exosomal microRNA-486-3p mediates acquired resistance to anaplastic lymphoma kinase inhibitor in EML4-ALK translocated lung adenocarcinoma

Abstract

Introduction: Cancer cells could release exosomes to modulate the activities of other cells in the tumour microenvironment or at distant metastatic sites. The microRNAs (miRNAs) in cancer-derived exosomes may modulate drug resistance in recipient cells. Anaplastic lymphoma kinase (ALK) gene rearrangement is one therapeutic target in lung adenocarcinoma that indicates response to treatment with ALK-tyrosine kinase inhibitors (ALK-TKI). The role of intratumoural heterogeneity in drug resistance remains elusive. Method: We have established ALK-translocated lung adenocarcinoma cell lines and subclones. Expressions of miRNAs were detected by quantitative real-time polymerase chain reaction. Cell viability was determined by MTT assay. Results: The exosomes from ALK-TKI-resistant subpopulation of lung cancer cells could reduce drug sensitivity in originally sensitive subpopulations. Circulating exosomal miR-486-3p was found to be correlated with disease progression of EML4-ALK-translocated lung adenocarcinoma patient on ALK-TKI treatment. Conclusion: Exosomes released by drug-resistant subpopulation could induce resistance of other subpopulation of cells. Exosomal miRNA may serve as a novel therapeutic strategy and circulating prognostic marker for ALKtranslocated lung cancer.