Identification of Tissue microRNAs Predictive of Sunitinib Activity in Patients with Metastatic Renal Cell Carcinoma

Abstract

PurposeTo identify tissue microRNAs predictive of sunitinib activity in patients with metastatic renal-cell-carcinoma (MRCC) and to evaluate in vitro their mechanism of action in sunitinib resistance.MethodsWe screened 673 microRNAs using TaqMan Low-density-Arrays (TLDAs) in tumors from MRCC patients with extreme phenotypes of marked efficacy and resistance to sunitinib, selected from an identification cohort (n = 41). The most relevant differentially expressed microRNAs were selected using bioinformatics-based target prediction analysis and quantified by qRT-PCR in tumors from patients presenting similar phenotypes selected from an independent cohort (n = 101). In vitro experiments were conducted to study the role of miR-942 in sunitinib resistance.ResultsTLDAs identified 64 microRNAs differentially expressed in the identification cohort. Seven candidates were quantified by qRT-PCR in the independent series. MiR-942 was the most accurate predictor of sunitinib efficacy (p = 0.0074). High expression of miR-942, miR-628-5p, miR-133a, and miR-484 was significantly associated with decreased time to progression and overall survival. These microRNAs were also overexpressed in the sunitinib resistant cell line Caki-2 in comparison with the sensitive cell line. MiR-942 overexpression in Caki-2 up-regulates MMP-9 and VEGF secretion which, in turn, promote HBMEC endothelial migration and sunitinib resistance.ConclusionsWe identified differentially expressed microRNAs in MRCC patients presenting marked sensitivity or resistance to sunitinib. MiR-942 was the best predictor of efficacy. We describe a novel paracrine mechanism through which high miR-942 levels in MRCC cells up-regulates MMP-9 and VEGF secretion to enhance endothelial migration and sunitinib resistance. Our results support further validation of these miRNA in clinical confirmatory studies.

The epigenetic landscape of renal cancer

“…These findings are consistent with the observation that primary and metastatic tumours remain epigenetically similar 237 . Several studies have analysed the presence of multiple mi RNAs in serum from patients with RCC to provide prognostic information and identify renal-specific cancers [240][241][242] . The use of miRNA profiles to predict treatment response has also been proposed and two studies have identified panels of mi RNAs that are associated with different responses to sunitinib, an FDA-approved treatment for RCC 243,244 .…”

A decade of pharmacogenomics research on tyrosine kinase inhibitors in metastatic renal cell cancer: a systematic review

“…Also, Berkers et al [58] showed that miRNA was related to the response to sunitinib as tested in 20 mRCC patients: a significantly lower expression of miRNA-141 was observed for poor responders [58]. On miRNA expression of miRNA, Prior et al [59] identified miRNA-942, miR-628-5p, miR133a, and miR-484 as predictors for sunitinib efficacy (i.e. time to progression, OS, and resistance).…”

“…time to progression, OS, and resistance). It was postulated that high levels of miRNA-942 will stimulate the secretion of matrix metalloproteinase-9 and VEGF and thereby effectuate resistance to sunitinib [59].…”

A mikroRNS-ek jelenléte vesetumorokban és lehetséges diagnosztikai-prognosztikai szerepük

“…Egyik tanulmány szerint a miR-141 a sunitinib kezelésre nehezen reagáló eseteknél jelentősen downreguláltnak mutatkozott (9,30). Egy másik elemzés alapján a miR-942 volt a legpontosabb előrejelzője a sunitinib érzékenységnek (31). Magas miR-942, -628-5p, -133a és -484 expressziója jelentősen ösz-szefügg a metasztatikus Rcc-esetek előrehaladásával, valamint a túléléssel is, amit az is igazol, hogy ezek a miR-ek a sunitinib rezisztens cAKI-2 humán Rcc-sejtvonalban is abnormális mértékben expresszálódtak az érzékeny sejtvonalhoz képest (9,31).…”

“…Egy másik elemzés alapján a miR-942 volt a legpontosabb előrejelzője a sunitinib érzékenységnek (31). Magas miR-942, -628-5p, -133a és -484 expressziója jelentősen ösz-szefügg a metasztatikus Rcc-esetek előrehaladásával, valamint a túléléssel is, amit az is igazol, hogy ezek a miR-ek a sunitinib rezisztens cAKI-2 humán Rcc-sejtvonalban is abnormális mértékben expresszálódtak az érzékeny sejtvonalhoz képest (9,31). A közelmúltban lett igazolva a miR-199a-3p sejtproliferációt gátló és a sejtciklus G1 fázisát blokkoló tulajdonsága a cAKI-1 Rcc-sejtvonalban (32).…”