MicroRNAs (miRNAs) as predictors of extreme response to tyrosine kinase inhibitors in renal cell cancer (RCC).

Abstract

e16076 Background: A number of different drugs are approved for the 1stline treatment of mRCC and provide a median PFS of ≈ 11 months. Yet, a small subset of pts will present an unusually either short or prolong response [extreme responders]. MiRNAs are small fragments of RNA that modulate gene expression controlling cell development and differentiation. Promising results about their value as predictors of drug response have been published in lung and colorectal cancer [Molina-Pinelo]. This study aims to define miRNA profiles in RCC and determine whether they can predict “extreme responses”. Methods: The expression of 754 miRNAs was analyzed with TaqMan Low Density Array Human MicroRNA Panel (TLDA) (ThermoFisher). QPCR was carried out in the System of Gene Expression and Genotyping Arrays module ViiA7. We defined long-term response pts (LR) (PFS˃11 months, n = 7) and primary refractory pts (PR) (progression as best response, n = 8). MiRNAs differentially expressed were independently analyzed by individual qPCR assays in the study cohort and in an external validation cohort of pts (n = 35). Statistical analysis was performed with SPSSv20. Results: Four miRNAs were significantly associated with patient response and differentially expressed in PR vs LR (up-regulated in PR: miR-425-5p, down-regulated in PR: miR-139-3p, let-7d and let-7e). Let-7d and let-7e were validated internally (p < 0.05) and all of them showed the same tendency but without statistically significance in the external validation cohort. Fourteen miRNAs had differential expression in tumor vs healthy tissue and seven were validated in the study cohort (tumor up-regulated: miR-146b, miR-21, miR-155, miR-122; tumor down-regulated: miR-135a, miR-200c and miR-187). When externally validated four (miR-135a, miR-200c, miR-187 and miR-21) (p < 0.05) were confirmed. Conclusions: MiRNAs could represent a valid predictive biomarker in the development of RCC and its treatment. These results have been validated in an independent cohort. MiRNAs regulation in PR vs LR patients need to continue being validated in a more extensive cohort of pts.