Department of Gastroenterology, Asan Liver Center, Asan Medical Center, University of Ulsan College of Medicine, 88 Olympic-ro 43-gil, Songpa-gu, Seoul, 05505, South Korea.
Department of Pathology, Asan Liver Center, Asan Medical Center, University of Ulsan College of Medicine, 88 Olympic-ro 43-gil, Songpa-gu, Seoul, South Korea.
J Cancer Res Clin Oncol. 2018 Aug;144(8):1487-1501. doi: 10.1007/s00432-018-2672-y. Epub 2018 Jun 1.
Although sorafenib enhances overall survival, sorafenib resistance has been reported to be a significant limiting factor for improved prognosis in patients with hepatocellular carcinoma (HCC). Therefore, it is important to identify the mechanism of sorafenib resistance. This study aimed to identify the causative factor of sorafenib resistance and suggest methods for overcoming it.
The sensitivity to sorafenib was compared in human HCC cell lines and patient-derived HCC primary cells. Based on its cytotoxicity, signaling pathways altered by sorafenib and the causative factors were examined through assays. The mechanism by which sorafenib modified the sorafenib-resistance inducer through gene or protein expression or stability was also investigated. We also designed a treatment option to overcome sorafenib resistance.
Sorafenib activated the Raf/MEK/ERK pathway and caused sorafenib resistance in HCC cell lines and patient-derived HCC primary cells. Sorafenib reactivated the MAPK pathway by down-regulating RKIP at the post-translational level. Knockdown of RKIP increased phosphorylated ERK and thus suppressed sorafenib-mediated cell death. We also found that sorafenib-reactivated ERK maybe an attractive target for second-line therapy for patients with sorafenib resistance. Sequential combination treatment with sorafenib and PD98059 significantly reduced the viability and proliferation of sorafenib-resistant cells, while their increasing apoptosis efficacy.
Reactivation of the Raf/MEK/ERK pathway through aberrant expression of RKIP is one of the mechanisms behind sorafenib resistance in HCC. Sequential combination treatment with sorafenib and PD98059 could provide a new strategy to overcome sorafenib resistance in future clinical studies.
尽管索拉非尼可提高总生存期，但已有研究报道索拉非尼耐药是影响肝细胞癌（HCC）患者预后改善的重要限制因素。因此，明确索拉非尼耐药的机制非常重要。本研究旨在确定索拉非尼耐药的原因，并提出克服耐药的方法。
比较人 HCC 细胞系和患者来源的 HCC 原代细胞对索拉非尼的敏感性。根据其细胞毒性，通过实验检测索拉非尼改变的信号通路和致病因素。还研究了索拉非尼通过基因或蛋白表达或稳定性改变来修饰索拉非尼耐药诱导剂的机制。我们还设计了一种克服索拉非尼耐药的治疗方案。
索拉非尼激活了 Raf/MEK/ERK 通路，并在 HCC 细胞系和患者来源的 HCC 原代细胞中导致索拉非尼耐药。索拉非尼通过在翻译后水平下调 RKIP 重新激活 MAPK 通路。RKIP 敲低增加了磷酸化 ERK，从而抑制了索拉非尼介导的细胞死亡。我们还发现，索拉非尼重新激活的 ERK 可能是索拉非尼耐药患者二线治疗的一个有吸引力的靶点。索拉非尼与 PD98059 序贯联合治疗可显著降低索拉非尼耐药细胞的活力和增殖，同时增加其凋亡效果。
通过 RKIP 的异常表达重新激活 Raf/MEK/ERK 通路是 HCC 中索拉非尼耐药的机制之一。索拉非尼与 PD98059 的序贯联合治疗可能为未来的临床研究提供克服索拉非尼耐药的新策略。
