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

Article type: Research Article

Authors: Janpipatkul, Keatdamrong^{a; b; c} | Trachu, Narumol^d | Watcharenwong, Piyakarn^e | Panvongsa, Wittaya^{b; f} | Worakitchanon, Wittawin^{a; b} | Metheetrairut, Chanatip^g | Oranratnachai, Songporn^{e; h} | Reungwetwattana, Thanyanan^e | Chairoungdua, Arthit^{a; b; f; i; *}

Affiliations: [a] Department of Physiology, Faculty of Science, Mahidol University, Bangkok, Thailand | [b] Excellent Center for Drug Discovery, Mahidol University, Bangkok, Thailand | [c] Department of Basic Medical Science, Faculty of Medicine Vajira Hospital, Navamindradhiraj University, Bangkok, Thailand | [d] Research Center, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, Thailand | [e] Division of Medical Oncology, Department of Medicine, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, Thailand | [f] Toxicology Graduate Program, Faculty of Science, Mahidol University, Bangkok, Thailand | [g] Department of Biochemistry, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand | [h] Oncology Clinic, Sriphat Medical Center, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand | [i] Center of Excellence on Environmental Health and Toxicology, Faculty of Science, Mahidol University, Bangkok, Thailand

Correspondence: [*] Corresponding author: Arthit Chairoungdua, Department of Physiology, Faculty of Science, Mahidol University, Rama 6 Rd., Ratchathewi, Bangkok 10400, Thailand. Tel.: +66 2 201 5615; Fax: +66 2 354 7154; E-mail: arthit.chi@mahidol.ac.th.

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-5189-5p 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.

Keywords: Osimertinib resistance, NSCLC, exosome, miRNA, biomarker

DOI: 10.3233/CBM-203075

Journal: Cancer Biomarkers, vol. 31, no. 3, pp. 281-294, 2021