Exosome-Transmitted lncARSR Promotes Sunitinib Resistance in Renal Cancer by Acting as a Competing Endogenous RNA

Cancer Cell. 2016 May 9;29(5):653-668. doi: 10.1016/j.ccell.2016.03.004. Epub 2016 Apr 21.

Abstract

Sunitinib resistance is a major challenge for advanced renal cell carcinoma (RCC). Understanding the underlying mechanisms and developing effective strategies against sunitinib resistance are highly desired in the clinic. Here we identified an lncRNA, named lncARSR (lncRNA Activated in RCC with Sunitinib Resistance), which correlated with clinically poor sunitinib response. lncARSR promoted sunitinib resistance via competitively binding miR-34/miR-449 to facilitate AXL and c-MET expression in RCC cells. Furthermore, bioactive lncARSR could be incorporated into exosomes and transmitted to sensitive cells, thus disseminating sunitinib resistance. Treatment of sunitinib-resistant RCC with locked nucleic acids targeting lncARSR or an AXL/c-MET inhibitor restored sunitinib response. Therefore, lncARSR may serve as a predictor and a potential therapeutic target for sunitinib resistance.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents / pharmacology
  • Blotting, Northern
  • Carcinoma, Renal Cell / blood
  • Carcinoma, Renal Cell / drug therapy*
  • Carcinoma, Renal Cell / genetics
  • Cell Line
  • Cell Line, Tumor
  • Disease-Free Survival
  • Drug Resistance, Neoplasm / genetics*
  • Exosomes / genetics*
  • Gene Expression Profiling / methods
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Indoles / pharmacology*
  • Kidney Neoplasms / blood
  • Kidney Neoplasms / drug therapy*
  • Kidney Neoplasms / genetics
  • Mice, Nude
  • MicroRNAs / genetics
  • MicroRNAs / metabolism
  • Proto-Oncogene Proteins / genetics
  • Proto-Oncogene Proteins c-met / genetics
  • Pyrroles / pharmacology*
  • RNA, Long Noncoding / blood
  • RNA, Long Noncoding / genetics*
  • RNA, Long Noncoding / metabolism
  • RNA, Neoplasm / genetics
  • RNA, Neoplasm / metabolism
  • Receptor Protein-Tyrosine Kinases / genetics
  • Reverse Transcriptase Polymerase Chain Reaction
  • Signal Transduction / genetics
  • Sunitinib
  • Treatment Outcome
  • Xenograft Model Antitumor Assays / methods

Substances

  • Antineoplastic Agents
  • Indoles
  • MIRN34 microRNA, human
  • MIRN449 microRNA, human
  • MicroRNAs
  • Proto-Oncogene Proteins
  • Pyrroles
  • RNA, Long Noncoding
  • RNA, Neoplasm
  • long noncoding RNA ARSR, human
  • Proto-Oncogene Proteins c-met
  • Receptor Protein-Tyrosine Kinases
  • axl receptor tyrosine kinase
  • Sunitinib