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Cancers 2018, 10(9), 321; https://doi.org/10.3390/cancers10090321

miR-9-5p in Nephrectomy Specimens is a Potential Predictor of Primary Resistance to First-Line Treatment with Tyrosine Kinase Inhibitors in Patients with Metastatic Renal Cell Carcinoma

1
Department of Urology, Charité University Medicine Berlin, 10117 Berlin, Germany
2
Department of Hematology, Oncology and Tumor Immunology, Charité University Medicine Berlin, 10117 Berlin, Germany
3
Department of Pathology, Charité University Medicine Berlin, 10117 Berlin, Germany
4
Department of Signal Transduction, Invasion and Metastasis of Epithelial Cells, Max-Delbrueck-Center for Molecular Medicine in the Helmholtz Association, 13125 Berlin, Germany
5
Berlin Institute for Urologic Research, 10115 Berlin, Germany
These authors contributed equally to this work.
These authors share senior authorship.
*
Author to whom correspondence should be addressed.
Received: 20 July 2018 / Revised: 22 August 2018 / Accepted: 29 August 2018 / Published: 10 September 2018
(This article belongs to the Special Issue Cancer Biomarkers)
Full-Text   |   PDF [997 KB, uploaded 10 September 2018]   |  

Abstract

Approximately 20–30% of patients with metastatic renal cell carcinoma (mRCC) in first-line treatment with tyrosine kinase inhibitors (TKIs) do not respond due to primary resistance to this drug. At present, suitable robust biomarkers for prediction of a response are not available. Therefore, the aim of this study was to evaluate a panel of microRNAs (miRNAs) in nephrectomy specimens for use as predictive biomarkers for TKI resistance. Archived formalin-fixed, paraffin embedded nephrectomy samples from 60 mRCC patients treated with first-line TKIs (sunitinib, n = 51; pazopanib, n = 6; sorafenib, n = 3) were categorized into responders and non-responders. Using the standard Response Evaluation Criteria in Solid Tumors, patients with progressive disease within 3 months after the start of treatment with TKI were considered as non-responders and those patients with stable disease and complete or partial response under the TKI treatment for at least 6 months as responders. Based on a miRNA microarray expression profile in the two stratified groups of patients, seven differentially expressed miRNAs were validated using droplet digital reverse-transcription quantitative real-time polymerase chain reaction (RT-qPCR) assays in the two groups. Receiver operating characteristic curve analysis and binary logistic regression of response prediction were performed. MiR-9-5p and miR-489-3p were able to discriminate between the two groups. MiR-9-5p, as the most significant miRNA, improved the correct prediction of primary resistance against TKIs in comparison to that of conventional clinicopathological variables. The results of the decision curve analyses, Kaplan-Meier analyses and Cox regression analyses confirmed the potential of miR-9-5p in the prediction of response to TKIs and the prediction of progression-free survival after the initiation of TKI treatment. View Full-Text
Keywords: renal cell carcinoma; metastasis; tyrosine kinase inhibitors; sunitinib; primary resistance; microRNAs; prognostic indicator renal cell carcinoma; metastasis; tyrosine kinase inhibitors; sunitinib; primary resistance; microRNAs; prognostic indicator
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Ralla, B.; Busch, J.; Flörcken, A.; Westermann, J.; Zhao, Z.; Kilic, E.; Weickmann, S.; Jung, M.; Fendler, A.; Jung, K. miR-9-5p in Nephrectomy Specimens is a Potential Predictor of Primary Resistance to First-Line Treatment with Tyrosine Kinase Inhibitors in Patients with Metastatic Renal Cell Carcinoma. Cancers 2018, 10, 321.

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