miR-155 and miR-484 Are Associated with Time to Progression in Metastatic Renal Cell Carcinoma Patients Treated with Sunitinib

Introduction

Tyrosine kinase inhibitors (TKIs) are widely used in the treatment of metastatic renal cell carcinoma (mRCC). The main effect of TKIs is mediated through the inhibition of angiogenesis. Almost all patients will develop resistance to the anti- VEGF effect during the treatment. MiRNAs, potent regulators of gene expression, could be suitable predictive markers. Our study was focused on finding tissue miRNAs associated with time to progression (TTP) of mRCC in patients treated with sunitinib.

Materials/methods

The study was approved by the local Ethics Board and written informed consent was obtained. The screening and the validation cohort included 16, and 63 patients respectively. Response was assessed according to RECIST criteria after 9 months and patients were divided as follows: a) responders (CR, PR, SD), and b) non-responders (PD).

Tumor tissue was provided as FFPE samples. Total RNA was isolated and profiling of 667 miRNAs was conducted using TaqMan Low- Density Array (TLDA) technology. Validation was performed by qRTPCR. Expression data from TLDA were normalized using miR-625* and evaluated using Bioconductor Limma differential expression analysis. In validation cohort, data were normalized using miR 1233 and evaluated by ROC and Kaplan-Meier analysis followed by Log-rank test.

Results and conclusions

MiRNA profiling of tumor tissue of responders (N = 8), or nonresponders (N = 8) to sunitinib revealed 19 differentially expressed miRNAs. 6 of them (P-value < 0.01, CT < 35: miR-155, miR-374-5p, miR 324-3p, miR-484, miR-302c, miR- 888) were chosen for the verification on the independent cohort (N = 63) by qRT-PCR. Kaplan-Meier analysis indicates that lower levels of miR-155 (median TTP 12.8 vs. 5.8 months, P-value < 0.01) and miR- 484 (median TTP 8.9 vs. 5.8 months, P value < 0.05) are associated with increased TTP in patients on sunitinib treatment. These miRNAs might thus be connected with sunitinib resistance. MiR 155 is a known oncogene with direct impact on angiogenesis. The role of miR- 484 in mRCC remains to be clarified. Stratification of patients based on miRNA analysis would allow more personalized approach in mRCC therapy.

The project was supported by Czech Ministry of Health (MZCR NT/13547- 4/2012 and NV15-34678A), by internal university grant (MUNI/A/1116/2014) and by CEITEC - Central European Institute of Technology (CZ.1.05/1.1.00/02.0068).