Abstract
BackgroundPrimary or acquired resistance to cetuximab often occurs during targeted therapy in metastatic colorectal cancer (mCRC) patients. In many cancers, the key role of the long noncoding RNA (lncRNA) urothelial carcinoma-associated 1 (UCA1) in anticancer drug resistance has been confirmed. Emerging evidence has shown that specific exosomal lncRNAs may serve as meaningful biomarkers. In this study, we hypothesize that exosomal UCA1 might predict the response to cetuximab in CRC patients.MethodsFirst, acquired cetuximab-resistant cell lines were generated, and UCA1 expressions in these cells and their exosomes were compared. We also systematically evaluate the stability of exosomal UCA1. Thereafter, the predictive value of exosomal UCA1 in CRC patients treated with cetuximab was evaluated. Finally, through cell apoptosis assays and immunofluorescence staining, we analyzed the role of UCA1-containing exosomes in conferring cetuximab resistance.ResultsUCA1 expression was markedly higher in cetuximab-resistant cancer cells and their exosomes. Exosomal UCA1 was shown to be detectable and stable in serum from CRC patients. In addition, circulating UCA1-containing exosomes could predict the clinical outcome of cetuximab therapy in CRC patients, and UCA1 expression was considerably higher in the progressive disease/stable disease patients than in the partial response/complete response patients. Furthermore, exosomes derived from cetuximab-resistant cells could alter UCA1 expression and transmit cetuximab resistance to sensitive cells.ConclusionsWe discovered a novel role of UCA1-containing exosomes, showed their capability to transmit drug resistance and investigated their potential clinical use in predicting cetuximab resistance.
Highlights
Primary or acquired resistance to cetuximab often occurs during targeted therapy in metastatic colorectal cancer patients
We detected urothelial carcinoma-associated 1 (UCA1) levels in exosomes derived from Caco2CR cells (CR-exo) and Caco2-CS cells (CS-exo) and found that UCA1 levels were significantly upregulated in complete response (CR)-exo compared with CS-exo (Fig. 1g)
(~ 20-fold) was much greater than that between Caco2CR and Caco2-CS cells (~ 7-fold), indicating that UCA1 was concentrated in exosomes derived from Caco2-CR cells; UCA1 expressions may be related to cetuximab resistance in Colorectal cancer (CRC) cells
Summary
Primary or acquired resistance to cetuximab often occurs during targeted therapy in metastatic colorectal cancer (mCRC) patients. The key role of the long noncoding RNA (lncRNA) urothelial carcinoma-associated 1 (UCA1) in anticancer drug resistance has been confirmed. MET amplification [7, 8], are robustly correlated with cetuximab resistance. Despite these genetic biomarkers, additional mechanisms of resistance to EGFR mAb are thought to be present in mCRC. Emerging evidence has demonstrated that lncRNAs play significant roles in biological processing, including cell cycle regulation, apoptosis and tumor invasion [11]. Other lncRNAs have been shown to play functional roles in resistance to targeted therapy [12]. Some lncRNAs could be potentially used as early diagnostic, prognostic and drug response biomarkers in malignant tumors [12,13,14]
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