Molecular Profiling of Druggable Targets in Clear Cell Renal Cell Carcinoma Through Targeted RNA Sequencing

Frontiers in Oncology

Martijn Huynen¹  Corina N. A. M. van den Heuvel²  William P. J. Leenders²  Anne van Ewijk²  Carolien Zeelen³  Tessa de Bitter³  Egbert Oosterwijk⁴  Peter Mulders⁴ 

[1] Center for Molecular and Biomolecular Informatics, Radboud Institute for Molecular Life Sciences, Nijmegen, Netherlands;Department of Biochemistry, Radboud Institute for Molecular Life Sciences, Nijmegen, Netherlands;Department of Pathology, Radboud University Medical Centre, Nijmegen, Netherlands;Department of Urology, Radboud University Medical Centre, Nijmegen, Netherlands;

关键词: cancer;    renal cell carcinoma;    diagnostics;    prognostics;    precision therapy;    RNA-sequencing;   

DOI  :  10.3389/fonc.2019.00117

来源: DOAJ

【 摘 要 】

Clear cell renal cell carcinoma (ccRCC) comprises more than 80% of all renal cancers and when metastasized leads to a 5-year survival rate of only 10%. The high rate of therapy failure and resistance development calls for reliable methods that provide information on the actionable biological pathways and predict optimal treatment protocols for individual patients. We here applied targeted RNA sequencing (t/RNA-NGS) using single molecule Molecular Inversion Probes on tumor nephrectomy samples of five ccRCC patients, comparing tumor with healthy kidney tissues. Transcriptome profiling focused on expression of genes with involvement in ccRCC biology that can be targeted with clinically available drugs. Results confirm high expression of vascular endothelial growth factor-A (VEGF-A) in tumor tissue relative to healthy-appearing kidney, in line with the angiogenic nature of ccRCC. PDGFRα and KIT, targets of the multi-kinase inhibitor sunitinib which is one of the current choices of first-line drug in metastasized ccRCC patients, were expressed at relatively low levels in tumor tissues, whereas significantly increased in normal kidney. Of all measured druggable tyrosine kinases, MET, AXL, or EGFR were expressed at higher levels in tumors than in normal kidney tissues, although intertumor differences were observed. Using cancer cell lines we show that t/RNA-NGS gene expression profiles can be used to predict in vitro sensitivity to targeted drugs. In conclusion, t/RNA-NGS analysis may provide insights into the (druggable) molecular make-up of individual renal cancers, and may guide personalized therapy of renal cell cancers.

【 授权许可】

Unknown