Integrated mRNA and miRNA Transcriptomic Analyses Reveals Divergent Mechanisms of Sunitinib Resistance in Clear Cell Renal Cell Carcinoma (ccRCC)

Cancers

Jose I. López¹  Ane Rubio²  María Armesto²  Charles H. Lawrie²  Lorea Manterola²  Maitane Marquez²  María Arestin²  Peio Errarte³ 

[1] Department of Pathology, Cruces University Hospital, 48903 Barakaldo, Spain;Molecular Oncology Group, Biodonostia Research Institute, 20014 San Sebastián, Spain;Onena Medicines S.L., 20014 San Sebastián, Spain;

关键词: renal cancer;    sunitinib;    resistance;    miRNA;    transcriptome;    pathway analysis;   

DOI  :  10.3390/cancers13174401

来源: DOAJ

【 摘 要 】

The anti-angiogenic therapy sunitinib remains the standard first-line treatment for meta static clear cell renal cell carcinoma (ccRCC). However, acquired resistance develops in nearly all responsive patients and represents a major source of treatment failure. We used an integrated miRNA and mRNA transcriptomic approach to identify miRNA:target gene interactions involved in sunitinib resistance. Through the generation of stably resistant clones in three ccRCC cell lines (786-O, A498 and Caki-1), we identified non-overlapping miRNA:target gene networks, suggesting divergent mechanisms of sunitinib resistance. Surprisingly, even though the genes involved in these networks were different, they shared targeting by multiple members of the miR-17~92 cluster. In 786-O cells, targeted genes were related to hypoxia/angiogenic pathways, whereas, in Caki-1 cells, they were related to inflammatory/proliferation pathways. The immunotherapy target PD-L1 was consistently up-regulated in resistant cells, and we demonstrated that the silencing of this gene resulted in an increase in sensitivity to sunitinib treatment only in 786-O-resistant cells, suggesting that some ccRCC patients might benefit from combination therapy with PD-L1 checkpoint inhibitors. In summary, we demonstrate that, although there are clearly divergent mechanisms of sunitinib resistance in ccRCC subtypes, the commonality of miRNAs in multiple pathways could be targeted to overcome sunitinib resistance.

【 授权许可】

Unknown