Vascular endothelial growth factor (
VEGF) and
mammalian target of rapamycin are well-known therapeutic targets for
renal cell carcinoma (RCC).
Sunitinib is an agent that targets
VEGF receptors and is considered to be a standard treatment for metastatic or unresectable clear cell RCC (ccRCC). However, ccRCC eventually develops resistance to
sunitinib in most cases, and the mechanisms underlying this resistance are not fully elucidated. In the present study, we established unique primary xenograft models, KURC1 (Kyoto University
Renal Cancer 1) and KURC2, from freshly isolated ccRCC specimens. The KURC1 xenograft initially responded to
sunitinib treatment, however finally acquired resistance. KURC2 retained sensitivity to
sunitinib for over 6 months. Comparing gene expression profiles between the two xenograft models with different sensitivity to
sunitinib, we identified
interleukin 13 receptor alpha 2 (IL13RA2) as a candidate molecule associated with the acquired
sunitinib-resistance in ccRCC. And patients with high IL13RA2 expression in immunohistochemistry in primary ccRCC
tumor tends to have
sunitinib-resistant metastatic site. Next, we showed that
sunitinib-sensitive 786-O cells acquired resistance in vivo when IL13RA2 was overexpressed. Conversely,
shRNA-mediated knockdown of IL13RA2 successfully overcame the
sunitinib-resistance in Caki-1 cells. Histopathological analyses revealed that IL13RA2 repressed
sunitinib-induced apoptosis without increasing
tumor vasculature in vivo. To our knowledge, this is a novel mechanism of developing resistance to
sunitinib in a certain population of ccRCC, and these results indicate that IL13RA2 could be one of potential target to overcome
sunitinib resistance.