AB071. The role of long non-coding RNAs in sunitinib resistance of renal cancer

Background: The incidence of renal cell carcinoma (RCC) has been rising throughout the world. Approximately 20% of RCC patients presented with advanced stage disease at the time of diagnosis, and in patients with localized RCC, nearly 30% will develop recurrence and metastasis after tumor resection. Recently, improved comprehension of RCC pathogenesis led to the development of receptor tyrosine kinase (RTK) inhibitors, such as sunitinib, as the mainstay of therapeutic options for advanced RCC patients. Sunitinib is an oral multi-targeted RTK inhibitor, which has potent anti-angiogenic effects and direct anti-tumor activities due to the inhibition of vascular endothelial growth factor receptor (VEGFR), platelet-derived growth factor receptors (PDGFR), stem-cell growth factor receptor (KIT) and FMS-like tyrosine kinase 3 (FLT3). However, 10–20% of advanced RCC patients are inherently refractory to sunitinib therapy, and most of the remaining patients end up with drug resistance and tumor progression after 6–15 months of therapy, resulting in failure of sunitinib to efficiently prolong the survival of RCC patients. Several studies have proposed the activation of compensatory signaling pathways for the acquisition of sunitinib resistance, but the picture remains unclear. On the other hand, few prognostic factors have been validated as predictive biomarkers of sunitinib response. Thus, it is urgent to elucidate the underlying mechanisms of sunitinib resistance and discover reliable biomarkers that can predict sunitinib response in RCC patients.

Methods: Exosomes can be secreted from multiple types of cells and participate in intercellular communication by transmitting intracellular cargoes, such as proteins and nucleic acids. Increasingly, some studies have suggested that exosomes from stromal cells could potentially affect therapeutic response though transfer of proteins and miRNAs. However, whether exosomes derived from resistant cancer cells can confer drug resistance to sensitive cells needs to be illustrated. Moreover, components embedded in circulating exosomes may serve as easily accessible biomarkers for the evaluation of drug response in patients. Long non-coding RNA (lncRNA) is a heterogeneous class of transcripts with a minimum length of 200 bases and without protein-coding potential. lncRNAs are involved in multilevel regulation of gene expression, including transcriptional regulation by recruiting chromatin-modifying complexes and post-transcriptional regulation by interacting with miRNAs, mRNAs or proteins. Emerging evidence supports the notion that lncRNAs modulate numerous hallmarks of cancer, including proliferation, apoptosis, metastasis and metabolism. However, the roles of lncRNAs in sunitinib resistance are poorly understood. In this study, we identify an upregulated lncRNA (lncARSR) in sunitinib-resistant RCC cells. We then investigate the contributions of lncARSR to sunitinib resistance and its therapeutic implications for sunitinib-resistant RCC patients.

Results: Herein we identified an lncRNA, named lncARSR (lncRNA Activated in RCC with Sunitinib Resistance), that 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 (LNA) targeting lncARSR or an AXL/c-MET inhibitor restored sunitinib response.

Conclusions: lncARSR may serve as a predictor and a potential therapeutic target for sunitinib resistance.

Keywords: Sunitinib; renal cancer; receptor tyrosine kinase (RTK); long non-coding RNA (lncRNA)