Exosomal microRNAs as potential biomarkers for osimertinib resistance of non-small cell lung cancer patients

Abstract

BACKGROUND: Osimertinib is an epidermal growth factor receptor-tyrosine kinase inhibitor that specifically targets the T790M mutation in cancer.Unfortunately, most non-small cell lung cancer (NSCLC) patients develop osimertinib resistance. Currently, the molecular biomarkers for monitoring osimertinib resistance are not available. OBJECTIVE: This study aimed to examine the profile of exosomal miRNA in the plasma of osimertinib-resistant NSCLC patients. METHODS: Plasma exosomal miRNA profiles of 8 NSCLC patients were analyzed by next-generation sequencing at osimertinib-sensitive and osimertinib-resistance stage.The expression of dysregulated exosomal miRNAs was validated and confirmed in another cohort of 19 NSCLC patients by qPCR The relationship between exosomal miRNA upregulation and clinical prognosis, survival analysis was evaluated by Kaplan-Meier curves. RESULTS: In osimertinib-resistant NSCLC patients, 10 exosomal miRNAs were significantly dysregulated compared to baseline. Upregulation of all 10 candidate exosomal miRNAs tended to correlate with increased latency to treatment failure and improved overall survival. Among them, 4 exosomal miRNAs, miR-323-3p, miR-1468-3p, miR-5189-3p and miR-6513-5p were essentially upregulated and show the potential to be markers for the discrimination of osimertinib-resistance from osimertinib-sensitive NSCLC patients with high accuracy (p< 0.0001). CONCLUSIONS: Our results highlight the potential role of these exosomal miRNAs as molecular biomarkers for the detection of osimertinib resistance.

Tumor-derived exosomes: immune properties and clinical application in lung cancer

“…In addition, Li et al [85] showed that plasma exosomal miR-92b-3p was significantly increased in chemoresistant small cell lung cancer patients and might serve as a potential dynamic biomarker for monitoring the drug resistance. Exosomal miR-29a-3p and miR-150-5p were identified as circulating biomarkers during thoracic radiation therapy for NSCLC and were correlated with delivered radiation therapy dose [86] . At present, precision medicine based on immunotherapy and targeted therapy has given new hope for lung cancer patients.…”

“…The ensuing problems of drug resistance have gained much interest from the research community. For example, exosomal miR-323-3p, miR-1468-3p, miR-5189-5p, and miR-6513-5p were identified as potential biomarkers to discriminate between osimertinib-resistant and osimertinib-sensitive NSCLC patients [ 87 ] , and exosomal miR-210-3p secreted by osimertinib-resistant HCC827 and PC-9 cells was able to promote epithelial-mesenchymal transition and drug resistance in osimertinib-sensitive, EGFR mutant NSCLC cells [ 88 ] . Moreover, exosomal circRNA_102481 enhanced EGFR-TKIs resistance through the microRNA-30a-5p/ROR1 axis in NSCLC [ 89 ] .…”

Extracellular Vesicles and Cell Pathways Involved in Cancer Chemoresistance

“…In this regard, some examples of lung, prostate, and breast cancers will be described. Janpipatkul et al analyzed the vesicular miRNA profile of eight patients affected by non-small-cell lung cancer (NSCLS) [ 161 ]. The patients were diagnosed with advanced NSCLC with EGFR mutations and started treatment with osimertinib.…”

“…The patients were diagnosed with advanced NSCLC with EGFR mutations and started treatment with osimertinib. This drug is a third-generation inhibitor targeting the epidermal growth factor receptor tyrosine kinase (EGFR); it is used to treat a subgroup of NSCLS patients harboring the T790M-EGFR mutation [ 161 ]. It is reported that resistance could appear after 9–13 months of treatment [ 162 ].…”

“…It is reported that resistance could appear after 9–13 months of treatment [ 162 ]. The analysis of vesicular miRNAs isolated from blood samples indicated that miR-323-3p, miR-1468-3p, miR-5189-5p, and miR-6513-5p are suitable candidate biomarkers for the discrimination of osimertinib-resistant from osimertinib-sensitive NSCLC patients [ 161 ]. In another study, blood sampling was performed before Pt-based chemotherapy administration and repeated after the occurrence of chemoresistance in 19 NSCLC patients [ 14 ].…”