Epithelial-mesenchymal transition as a mechanism of resistance to tyrosine kinase inhibitors in clear cell renal cell carcinoma

Abstract

Tyrosine kinase inhibitors (TKIs) are widely accepted as treatment for metastatic clear cell renal cell carcinoma (ccRCC). However, most patients eventually experience disease progression despite TKI treatment, even if the initial response is favorable. To define the underlying mechanism of TKI resistance, 10 TKI-treated metastatic ccRCC cases in which tumor samples were harvested before treatment and immediately after disease progression were examined. Gene expression profiles and copy number variations of matched pre- and post-treatment tumor samples were investigated. Altered biologic characteristics were confirmed in sunitinib-resistant ccRCC cell lines, which were generated by long-term treatment with sunitinib-containing media. Gene transcript levels related to the cell cycle and epithelial-mesenchymal transition (EMT) were significantly upregulated in the treated tumor samples compared with the pre-treatment samples. The mitotic count and sarcomatoid component were significantly increased in treated tumor samples. Alteration of EMT-related genes was also demonstrated in a sunitinib-resistant ccRCC cell line that showed enhanced migration and invasion compared to the parent cell line. siRNA-induced inhibition of EMT-related gene expression significantly suppressed the migration and invasion capacity of TKI-resistant cell lines. The present study shows that both ccRCC cases that progressed after TKI treatment and sunitinib-resistant ccRCC cell lines demonstrated alteration of EMT-related gene expression and enhancement of EMT-related behavior. These results suggest that EMT may explain the aggressive behavior of TKI-resistant ccRCC.