Splice variants of lysosome-associated membrane proteins 2A and 2B are involved in sunitinib resistance in human renal cell carcinoma cells

Abstract

Sunitinib, a tyrosine kinase inhibitor, is among the first-line treatments for metastatic or advanced stage renal cell carcinoma (RCC). However, patients with RCC develop resistance to sunitinib. We have previously demonstrated that lysosome-associated membrane protein 2 (LAMP-2), which has three splice variants with different functions (LAMP-2A, LAMP-2B, and LAMP-2C), is involved in RCC. In the present study, we examined which splice variants of LAMP-2 contributed to sunitinib resistance in RCC cells. In vitro analysis using ACHN, human RCC cell line, revealed that the IC50 of sunitinib was significantly increased by overexpression of LAMP-2A and LAMP-2B, but not LAMP-2C (P<0.01). Kaplan-Meier survival analysis using clinical samples revealed an association between shorter survival and high expression of LAMP-2A and LAMP-2B, but not LAMP-2C, in patients with RCC treated with sunitinib (P=0.01). Furthermore, high expression of LAMP-2A and LAMP-2B in RCC revealed a weak to moderate inverse correlation with the tumor shrinkage rate and progression-free survival, respectively. Thus, high expression of LAMP-2A and LAMP-2B contributed to the acquisition of sunitinib resistance, indicating that the expression of these two variants can predict the efficacy of sunitinib treatment in patients with RCC.