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

Area of Science:

• Oncology
• Genomics
• Translational Medicine

Background:

• Clear cell renal cell carcinoma (ccRCC) is the most common kidney cancer subtype, with poor prognosis upon metastasis.
• Therapy failure and resistance necessitate methods for identifying actionable biological pathways and predicting personalized treatment outcomes.

Purpose of the Study:

• To apply targeted RNA sequencing (t/RNA-NGS) for transcriptome profiling of ccRCC tumors.
• To identify actionable gene expression patterns in ccRCC for targeted drug selection.
• To assess the potential of t/RNA-NGS in predicting patient response to targeted therapies.

Main Methods:

• Targeted RNA sequencing (t/RNA-NGS) using single molecule Molecular Inversion Probes on tumor and healthy kidney tissues from five ccRCC patients.
• Transcriptome profiling focused on druggable genes relevant to ccRCC biology.
• Validation of predictive potential using cancer cell lines for *in vitro* drug sensitivity assays.

Main Results:

• Elevated vascular endothelial growth factor-A (VEGF-A) expression in ccRCC tumors, consistent with tumor angiogenesis.
• Lower expression of PDGFRα and KIT in tumors compared to normal kidney tissue, contrasting with sunitinib's target profile.
• Increased expression of MET, AXL, and EGFR in tumors versus normal kidney tissue, with observed inter-tumor heterogeneity.
• Demonstrated correlation between t/RNA-NGS profiles and *in vitro* drug sensitivity in cancer cell lines.

Conclusions:

• t/RNA-NGS provides insights into the druggable molecular landscape of individual ccRCC tumors.
• This approach holds promise for guiding personalized therapy selection in renal cell carcinoma.
• t/RNA-NGS may help overcome challenges of therapy failure and resistance in ccRCC treatment.