Abstract
BackgroundOsimertinib resistance limits the treatment of epidermal growth factor receptor-(EGFR)-mutated non-small-cell lung carcinoma (NSCLC). The mechanisms of osimertinib resistance need to be elucidated to determine alternative treatment strategies. This study explores the role of M2 type tumor-associated macrophage (TAM)-derived exosomal MSTRG.292666.16 in osimertinib resistance, and its related competing endogenous RNA (ceRNA) mechanism.MethodsM2 type TAMs were induced with 200 ng/mL phorbol 12-myristate 13-acetate, 20 ng/mL IL-4 and IL-13, and M2 type macrophage markers were measured by RT-qPCR. Next, the exosomes were isolated and characterized. Tumor formation in nude mice was conducted using H1975 cells under different treatment conditions. Small RNA sequencing was performed on exosomes derived from sensitive and resistant plasma, and ceRNA networks were constructed. Fluorescence in situ hybridization was used to observe the localization of MSTRG.292666.16, and a ceRNA network (MSTRG.292666.16-miR-6836-5p-MAPK8IP3) was selected for further validation.ResultsM2 type TAMs, and M2 type TAM-derived exosomes were successfully induced and isolated. Nude mice results showed that M2 type TAM-derived exosomes and MSTRG.292666.16 overexpression significantly increased tumor volume after administration of osimertinib for 4 weeks. M2 type TAMs were found in the resistant plasma, and MSTRG.292666.16 localized in the cytoplasm of H1975 cells. In addition, the genes in the ceRNA networks were significantly enriched in eight GO terms and seven KEGG pathways, including the MAPK signaling pathway. Subsequently, the levels of MSTRG.292666.16 and MAPK8IP3 significantly increased in both resistant plasma-derived exosomes and M2 type TAM-derived exosomes, while miR-6836-5p levels were significantly reduced. Finally, MSTRG.292666.16, miR-6836-5p, and MAPK8IP3 were part of the same network.ConclusionsM2 type TAM-derived exosomes promoted osimertinib resistance in NSCLC by regulating the MSTRG.292666.16/miR-6386-5p/MAPK8IP3 axis.
Highlights
Osimertinib resistance limits the treatment of epidermal growth factor receptor-(EGFR)-mutated non-small-cell lung carcinoma (NSCLC)
It was found that the expression levels of CD206, CD163, TGF-β, IL-10, and Arg-1 were significantly increased in the M2 type tumor-associated macrophage (TAM) compared with those in THP-1 cells (P < 0.05, Fig. 1), which indicated that M2 type TAMs were successfully induced by PMA, IL-4, and IL-13
TEM results showed that the exosomes isolated from the TPH-1 cells and M2 type TAMs were nearly round with a diameter of approximately 100 nm (Fig. 2A)
Summary
Osimertinib resistance limits the treatment of epidermal growth factor receptor-(EGFR)-mutated non-small-cell lung carcinoma (NSCLC). Surgery, chemotherapy, and radiation are the traditional treatments for lung cancer; or patients with advanced disease, surgery is not sufficient to restrain cancer progression [3]. With the continuous update of gene detection technology, epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) have become an essential method for precision treatment of NSCLC [4]. Recent studies have reported that the overall survival of patients with EGFR-mutated advanced NSCLC was up to 38.6 months after osimertinib treatment, and postoperative adjuvant therapy with osimertinib significantly increased disease-free survival [6, 7]. Osimertinib is a powerful tool in the first-line treatment of EGFR-mutated advanced NSCLC and in adjuvant therapy for NSCLC after surgery. Osimertinib resistance is a major obstacle in the treatment of NSCLC, and the resistance mechanisms have not been fully elucidated
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