Elucidating mechanisms of sunitinib resistance in renal cancer: an integrated pathological-molecular analysis

// Henriett Butz 1, 2 , Qiang Ding 1, 2 , Roy Nofech-Mozes 1 , Zsuzsanna Lichner 1, 2 , Heyu Ni 1, 2 and George M. Yousef 1, 2 1 Department of Laboratory Medicine, and The Keenan Research Centre for Biomedical Science of St. Michael's Hospital, Toronto, ON, M5B 1W8, Canada 2 Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, M5S 1A8, Canada Correspondence to: George M. Yousef, email: yousefg@smh.ca Keywords: sunitinib; resistance; miRNAs; renal cell carcinoma; metastasis Received: July 14, 2017 Accepted: November 15, 2017 Published: December 08, 2017 ABSTRACT Upon sunitinib treatment of metastatic renal cell carcinoma patients eventually acquire resistance. Our aim was to investigate microRNAs behind sunitinib resistance. We developed an in vivo xenograft and an in vitro model and compared morphological, immunhistochemical, transcriptomical and miRNome data changes during sunitinib response and resistance by performing next-generation mRNA and miRNA sequencing. Complex bioinformatics (pathway, BioFunction and network) analysis were performed. Results were validated by in vitro functional assays. Our morphological, immunhistochemical, transcriptomical and miRNome data all pointed out that during sunitinib resistance tumor cells changed to migratory phenotype. We identified the downregulated miR-1 and miR-663a targeting FRAS1 (Fraser Extracellular Matrix Complex Subunit 1) and MDGA1 (MAM Domain Containing Glycosylphosphatidylinositol Anchor 1) in resistant tumors. We proved firstly miR-1-FRAS1 and miR-663a-MDGA1 interactions. We found that MDGA1 knockdown decreased renal cancer cell migration and proliferation similarly to restoration of levels of miR-1 and miR-663. Our results support the central role of cell migration as an adaptive mechanism to secure tumor survival behind sunitinib resistance. MDGA1, FRAS1 or the targeting miRNAs can be potential adjuvant therapeutic targets, through inhibition of cancer cell migration, thus eliminating the development of resistance and metastasis.