BACKGROUND/AIM: Sunitinib is a tyrosine kinase inhibitor routinely used as first-line therapy in metastatic renal cell carcinoma (mRCC). Emerging evidence suggests that microRNAs (miRNAs) could be suitable biomarkers with predictive potential in mRCC. The aim of this study was to identify miRNA-based predictive biomarkers of therapy response to avoid unnecessary therapy to non-responding patients. PATIENTS AND METHODS: High-throughput miRNA microarray profiling was performed on a cohort of 47 patients treated with sunitinib. Validation of candidate miRNAs was carried out on an independent cohort of 132 mRCC patients using qRT-PCR. RESULTS: Out of 158 miRNAs (65 down-regulated, 93 up-regulated), six miRNAs were chosen for independent validation and miR-376b-3p was confirmed to be differentially expressed in tumors of patients with primary resistance versus long-term response (p<0.0002). CONCLUSION: A predictive miRNA associated with progression-free survival in metastatic renal cell carcinoma patients treated with sunitinib was identified.

Biomedical Center Faculty of Medicine in Pilsen Charles University Pilsen Czech Republic

Department of Clinical Oncology and Radiotherapy University Hospital in Hradec Kralove Hradec Kralove Czech Republic

Department of Oncology 1st Faculty of Medicine Charles University and Thomayer Hospital Prague Czech Republic

Department of Oncology and Radiotherapeutics Medical School and Teaching Hospital in Pilsen Charles University Pilsen Czech Republic

Institute for Biostatistics and Analyses Masaryk University Brno Czech Republic

Masaryk Memorial Cancer Institute Department of Comprehensive Cancer Care Faculty of Medicine Masaryk University Brno Czech Republic

Masaryk Memorial Cancer Institute Department of Oncological and Experimental Pathology Faculty of Medicine Masaryk University Brno Czech Republic

Masaryk University Central European Institute of Technology Brno Czech Republic

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Capitanio U, Bensalah K, Bex A, Boorjian SA, Bray F, Coleman J, Gore JL, Sun M, Wood C, Russo P. Epidemiology of renal cell carcinoma. Eur Urol. 2019;75(1):74–84. PMID: 30243799. DOI: 10.1016/j.eururo.2018.08.036. PubMed PMC

Bamias A, Escudier B, Sternberg CN, Zagouri F, Dellis A, Djavan B, Tzannis K, Kontovinis L, Stravodimos K, Papatsoris A, Mitropoulos D, Deliveliotis C, Dimopoulos MA, Constantinides CA. Current clinical practice guidelines for the treatment of renal cell carcinoma: A systematic review and critical evaluation. Oncologist. 2017;22(6):667–679. DOI: 10.1634/theoncologist.2016-0435. PubMed PMC

Motzer RJ, Hutson TE, Tomczak P, Michaelson MD, Bukowski RM, Oudard S, Negrier S, Szczylik C, Pili R, Bjarnason GA, Garcia-del-Muro X, Sosman JA, Solska E, Wilding G, Thompson JA, Kim ST, Chen I, Huang X, Figlin RA. Overall survival and updated results for sunitinib compared with interferon alfa in patients with metastatic renal cell carcinoma. J Clin Oncol. 2009;27(22):3584–3590. PMID: 19487381. DOI: 10.1200/JCO.2008.20.1293. PubMed PMC

Rini BI, Atkins MB. Resistance to targeted therapy in renal-cell carcinoma. Lancet Oncol. 2009;10(10):992–1000. PMID: 19796751. PubMed

Friedman RC, Farh KK-H, Burge CB, Bartel DP. Most mammalian mRNAs are conserved targets of microRNAs. Genome Res. 2009;19(1):92–105. PMID: 18955434. DOI: 10.1101/gr.082701.108. PubMed PMC

Petillo D, Kort EJ, Anema J, Furge KA, Yang XJ, Teh BT. MicroRNA profiling of human kidney cancer subtypes. Int J Oncol. 2009;35(1):109–114. PMID: 19513557. DOI: 10.3892/ijo_00000318. PubMed

Gu L, Li H, Chen L, Ma X, Gao Y, Li X, Zhang Y, Fan Y, Zhang X. MicroRNAs as prognostic molecular signatures in renal cell carcinoma: a systematic review and meta-analysis. Oncotarget. 2015;6:32545–32560. PMID: 26416448. DOI: 10.18632/ oncotarget.5324. PubMed PMC

Kovacova J, Juracek J, Poprach A, Buchler T, Kopecky J, Fiala O, Svoboda M, Slaby O. Candidate microRNA biomarkers of therapeutic response to sunitinib in metastatic renal cell carcinoma: a validation study in patients with extremely good and poor response. Anticancer Res. 2018;38(5):2961–2965. PMID: 29715124. DOI: 10.21873/anticanres.12546. PubMed

Pompas-Veganzones N, Sandonis V, Perez-Lanzac A, Beltran M, Beardo P, Juárez A, Vazquez F, Cozar JM, Alvarez-Ossorio JL, Sanchez-Carbayo M. Myopodin methylation is a prognostic biomarker and predicts antiangiogenic response in advanced kidney cancer. Tumour Biol. 2016;37(10):14301–14310. PMID: 27592258. DOI: 10.1007/s13277-016-5267-8. PubMed

Kim J, Hwang J, Jeong H, Song HJ, Shin J, Hur G, Park YW, Lee SH, Kim J. Promoter methylation status of VEGF receptor genes: a possible epigenetic biomarker to anticipate the efficacy of intracellular-acting VEGF-targeted drugs in cancer cells. Epigenetics. 2012;7(2):191–200. PMID: 22395469. DOI: 10.4161/epi.7.2.18973. PubMed

Motzer RJ, Hutson TE, Hudes GR, Figlin RA, Martini JF, English PA, Huang X, Valota O, Williams JA. Investigation of novel circulating proteins, germ line single-nucleotide polymorphisms, and molecular tumor markers as potential efficacy biomarkers of first-line sunitinib therapy for advanced renal cell carcinoma. Cancer Chemother Pharmacol. 2014;74(4):739–750. PMID: 25100134. DOI: 10.1007/s00280-014-2539-0. PubMed PMC

Rossi E, Fassan M, Aieta M, Zilio F, Celadin R, Borin M, Grassi A, Troiani L, Basso U, Barile C, Sava T, Lanza C, Miatello L, Jirillo A, Rugge M, Indraccolo S, Cristofanilli M, Amadori A, Zamarchi R. Dynamic changes of live/apoptotic circulating tumour cells as predictive marker of response to sunitinib in metastatic renal cancer. Br J Cancer. 2012;107(8):1286–1294. PMID: 22955853. DOI: 10.1038/bjc.2012.388. PubMed PMC

Lowery A, Han Z. Assessment of tumor response to tyrosine kinase inhibitors. Front Biosci (Landmark Ed) 2011;16:1996–2007. PMID: 21622159. PubMed PMC

Beuselinck B, Karadimou A, Lambrechts D, Claes B, Wolter P, Couchy G, Berkers J, van Poppel H, Paridaens R, Schöffski P, Méjean A, Verkarre V, Lerut E, Joly F, Lebret T, Gravis G, Deplanque G, Descazeaud A, Leclercq NR, Molinié V, Patard JJ, Teghom C, Elaidi R, Zucman Rossi J, Oudard S. VEGFR1 single nucleotide polymorphisms associated with outcome in patients with metastatic renal cell carcinoma treated with sunitinib – a multicentric retrospective analysis. Acta Oncol. 2014;53(1):103–112. PMID: 23421954. DOI: 10.3109/ 0284186X.2013.770600. PubMed

Decoster L, Vande Broek I, Neyns B, Majois F, Baurain JF, Rottey S, Rorive A, Anckaert E, De Mey J, De Brakeleer S, De Grève J. Biomarker analysis in a phase II study of sunitinib in patients with advanced melanoma. Anticancer Res. 2015;35(12):6893–6899. PMID: 26637913. PubMed

Pilskog M, Beisland C, Akslen LA, Bostad L, Haug Å, Heinrich D, Hjelle KM, Straume O. Predictive value of C-reactive protein in patients treated with sunitinib for metastatic clear cell renal cell carcinoma. BMC Urol. 2017;17(1):74. PMID: 28859644. DOI: 10.1186/s12894-017-0267-6. PubMed PMC

Grépin R, Guyot M, Giuliano S, Boncompagni M, Ambrosetti D, Chamorey E, Scoazec JY, Negrier S, Simonnet H, Pagès G. The CXCL7/CXCR1/2 axis is a key driver in the growth of clear cell renal cell carcinoma. Cancer Res. 2014;74(3):873–883. PMID: 24335961. DOI: 10.1158/0008-5472.CAN-13-1267. PubMed

Dufies M, Giuliano S, Viotti J, Borchiellini D, Cooley LS, Ambrosetti D, Guyot M, Ndiaye PD, Parola J, Claren A, Schiappa R, Gal J, Frangeul A, Jacquel A, Cassuto O, Grépin R, Auberger P, Bikfalvi A, Milano G, Escudier B, Rioux-Leclercq N, Porta C, Negrier S, Chamorey E, Ferrero JM, Pagès G. CXCL7 is a predictive marker of sunitinib efficacy in clear cell renal cell carcinomas. Br J Cancer. 2017;117(7):947–953. PMID: 28850564. DOI: 10.1038/bjc.2017.276. PubMed PMC

Calin GA, Liu CG, Sevignani C, Ferracin M, Felli N, Dumitru CD, Shimizu M, Cimmino A, Zupo S, Dono M, Dell'Aquila ML, Alder H, Rassenti L, Kipps TJ, Bullrich F, Negrini M, Croce CM. MicroRNA profiling reveals distinct signatures in B cell chronic lymphocytic leukemias. Proc Natl Acad Sci USA. 2004;101(32):11755–11760. PMID: 15284443. DOI: 10.1073/ pnas.0404432101. PubMed PMC

Heinzelmann J, Henning B, Sanjmyatav J, Posorski N, Steiner T, Wunderlich H, Gajda MR, Junker K. Specific miRNA signatures are associated with metastasis and poor prognosis in clear cell renal cell carcinoma. World J Urol. 2011;29(3):367–373. PMID: 21229250. DOI: 10.1007/s00345-010-0633-4. PubMed

Litière S, Collette S, de Vries EGE, Seymour L, Bogaerts J. RECIST - learning from the past to build the future. Nat Rev Clin Oncol. 2017;14(3):187–192. PMID: 27995946. DOI: 10.1038/nrclinonc.2016.195. PubMed

Kolesnikov N, Hastings E, Keays M, Melnichuk O, Tang YA, Williams E, Dylag M, Kurbatova N, Brandizi M, Burdett T, Megy K, Pilicheva E, Rustici G, Tikhonov A, Parkinson H, Petryszak R, Sarkans U, Brazma A. ArrayExpress update-simplifying data submissions. Nucleic Acids Res. 2015;43(Database issue):D1113–1136. PMID: 25361974. DOI: 10.1093/ nar/gku1057. PubMed PMC

Li L-J, Huang Q, Zhang N, Wang G-B, Liu Y-H. miR-376b-5p regulates angiogenesis in cerebral ischemia. Mol Med Rep. 2014;10(1):527–535. PMID: 24789343. DOI: 10.3892/mmr. 2014.2172. PubMed

Korkmaz G, le Sage C, Tekirdag KA, Agami R, Gozuacik D. miR-376b controls starvation and mTOR inhibition-related autophagy by targeting ATG4C and BECN1. Autophagy. 2012;8(2):165–176. PMID: 22248718. DOI: 10.4161/auto.8.2.18351. PubMed

Sun YL, Li SH, Yang L, Wang Y. miR-376b-3p attenuates mitochondrial fission and cardiac hypertrophy by targeting mitochondrial fission factor. Clin Exp Pharmacol Physiol. 2018;45:779–787. PMID: 29570827. DOI: 10.1111/1440-1681. 12938. PubMed

Berkers J, Govaere O, Wolter P, Beuselinck B, Schöffski P, van Kempen LC, Albersen M, Van den Oord J, Roskams T, Swinnen J, Joniau S, Van Poppel H, Lerut E. A possible role for microRNA-141 down-regulation in sunitinib resistant metastatic clear cell renal cell carcinoma through induction of epithelial-to-mesenchymal transition and hypoxia resistance. J Urol. 2013;189(5):1930–1938. PMID: 23206420. DOI: 10.1016/ j.juro.2012.11.133. PubMed

Liu R, Ma X, Xu L, Wang D, Jiang X, Zhu W, Cui B, Ning G, Lin D, Wang S. Differential microRNA expression in peripheral blood mononuclear cells from Graves’ disease patients. J Clin Endocrinol Metab. 2012;97(6):E968–972. PMID: 22456620. DOI: 10.1210/jc.2011-2982. PubMed

Kovacova J, Poprach A, Buchler T, Cho WC, Slaby O. MicroRNAs as predictive biomarkers of response to tyrosine kinase inhibitor therapy in metastatic renal cell carcinoma. Clin Chem Lab Med. 2018;56(9):1426–1431. PMID: 29451857. DOI: 10.1515/cclm-2017-0861. PubMed

Lukamowicz-Rajska M, Mittmann C, Prummer M, Zhong Q, Bedke J, Hennenlotter J, Stenzl A, Mischo A, Bihr S, Schmidinger M, Vogl U, Blume I, Karlo C, Schraml P, Moch H. MiR-99b-5p expression and response to tyrosine kinase inhibitor treatment in clear cell renal cell carcinoma patients. Oncotarget. 2016;7:78433–78447. PMID: 27738339. DOI: 10.18632/oncotarget.12618. PubMed PMC

Ralla B, Busch J, Flörcken A, Westermann J, Zhao Z, Kilic E, Weickmann S, Jung M, Fendler A, Jung K. miR-9-5p in nephrectomy specimens is a potential predictor of primary resistance to first-line treatment with tyrosine kinase inhibitors in patients with metastatic renal cell carcinoma. Cancers (Basel) 2018;10 PMID: 27738339. DOI: 10.18632/oncotarget.12618. PubMed PMC