Gao Hui, Deng Lichun
Medical College, Qingdao University, Qingdao, 266023, Shandong, China.
Cell Biochem Biophys. 2014 Mar;68(2):419-25. doi: 10.1007/s12013-013-9723-4.
Multi-target tyrosine kinase inhibitor Sunitinib has been widely used in cancer treatment, including metastatic renal cell carcinoma. However, most patients who initially benefit from Sunitinib develop resistance with extended usage of Sunitinib, which is referred to as "acquired resistance". The molecular mechanisms contributing to this acquired resistance remain poorly understood. In this present study, we established Sunitinib-resistant cell lines from human renal cell lines (786-O, A498, ACHN and CAKI1) by continuous treatment with Sunitinib to explore the molecular mechanism leading to Sunitinib resistance. We found that PDGFR-β expression in cell seems to be a protective factor against Sunitinib resistance formation. In addition, we found that both SK1 and ERK were activated in Sunitinib-resistance cell lines and SK1 and ERK inhibitors could resensitize Sunitinib-resistant cell lines. In conclusion, our observations suggest that SK1 and ERK activation is a feature of resistant cell lines, which serves as an alternative pathway evading anti-tumor activity of Sunitinib.
多靶点酪氨酸激酶抑制剂舒尼替尼已广泛应用于癌症治疗，包括转移性肾细胞癌。然而，大多数最初从舒尼替尼治疗中获益的患者在长期使用舒尼替尼后会产生耐药性，这被称为“获得性耐药”。导致这种获得性耐药的分子机制仍知之甚少。在本研究中，我们通过用舒尼替尼连续处理人肾癌细胞系（786 - O、A498、ACHN和CAKI1）建立了舒尼替尼耐药细胞系，以探索导致舒尼替尼耐药的分子机制。我们发现细胞中血小板衍生生长因子受体β（PDGFR - β）的表达似乎是抵抗舒尼替尼耐药形成的一个保护因素。此外，我们发现鞘氨醇激酶1（SK1）和细胞外信号调节激酶（ERK）在舒尼替尼耐药细胞系中均被激活，并且SK1和ERK抑制剂可使舒尼替尼耐药细胞系重新敏感。总之，我们的观察结果表明，SK1和ERK激活是耐药细胞系的一个特征，它作为逃避舒尼替尼抗肿瘤活性的一条替代途径。
