Division of Urology, Faculty of Medicine, Tottori University, Yonago, Tottori 683‑8503, Japan.
Division of Experimental Pathology, Faculty of Medicine, Tottori University, Yonago, Tottori 683‑8503, Japan.
Oncol Rep. 2020 Nov;44(5):1810-1820. doi: 10.3892/or.2020.7752. Epub 2020 Sep 4.
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.
舒尼替尼是一种酪氨酸激酶抑制剂，是转移性或晚期肾细胞癌 (RCC) 的一线治疗药物之一。然而，RCC 患者对舒尼替尼产生耐药性。我们之前已经证明，溶酶体相关膜蛋白 2（LAMP-2），其具有三种不同功能的剪接变体（LAMP-2A、LAMP-2B 和 LAMP-2C），与 RCC 有关。在本研究中，我们研究了 LAMP-2 的哪种剪接变体有助于 RCC 细胞对舒尼替尼产生耐药性。在 ACHN（一种人 RCC 细胞系）的体外分析中，发现 LAMP-2A 和 LAMP-2B 的过表达显著增加了舒尼替尼的 IC50，但 LAMP-2C 则不然（P<0.01）。对接受舒尼替尼治疗的 RCC 患者临床样本的 Kaplan-Meier 生存分析表明，LAMP-2A 和 LAMP-2B 的高表达与较短的生存期相关，而 LAMP-2C 则没有（P=0.01）。此外，RCC 中 LAMP-2A 和 LAMP-2B 的高表达与肿瘤退缩率和无进展生存期分别呈弱至中度负相关。因此，LAMP-2A 和 LAMP-2B 的高表达有助于获得舒尼替尼耐药性，表明这两种变体的表达可以预测 RCC 患者接受舒尼替尼治疗的疗效。
