Steele Laboratories for Tumor Biology, Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, USA.
Institute of Biomedical Engineering, National Tsing Hua University, Hsinchu, Taiwan.
Sci Rep. 2017 Mar 9;7:44123. doi: 10.1038/srep44123.
Sorafenib is a RAF inhibitor approved for several cancers, including hepatocellular carcinoma (HCC). Inhibition of RAF kinases can induce a dose-dependent "paradoxical" upregulation of the downstream mitogen-activated protein kinase (MAPK) pathway in cancer cells. It is unknown whether "paradoxical" ERK activation occurs after sorafenib therapy in HCC, and if so, if it impacts the therapeutic efficacy. Here, we demonstrate that RAF inhibition by sorafenib rapidly leads to RAF dimerization and ERK activation in HCCs, which contributes to treatment evasion. The transactivation of RAF dimers and ERK signaling promotes HCC cell survival, prevents apoptosis via downregulation of BIM and achieves immunosuppression by MAPK/NF-kB-dependent activation of PD-L1 gene expression. To overcome treatment evasion and reduce systemic effects, we developed CXCR4-targeted nanoparticles to co-deliver sorafenib with the MEK inhibitor AZD6244 in HCC. Using this approach, we preferentially and efficiently inactivated RAF/ERK, upregulated BIM and down-regulated PD-L1 expression in HCC, and facilitated intra-tumoral infiltration of cytotoxic CD8+ T cells. These effects resulted in a profound delay in tumor growth. Thus, this nano-delivery strategy to selectively target tumors and prevent the paradoxical ERK activation could increase the feasibility of dual RAF/MEK inhibition to overcome sorafenib treatment escape in HCC.
索拉非尼是一种 RAF 抑制剂，已被批准用于多种癌症，包括肝细胞癌（HCC）。RAF 激酶的抑制作用会导致癌细胞下游丝裂原活化蛋白激酶（MAPK）途径的剂量依赖性“反常”上调。目前尚不清楚 HCC 患者在接受索拉非尼治疗后是否会发生“反常”ERK 激活，如果发生，是否会影响治疗效果。在这里，我们证明索拉非尼对 RAF 的抑制作用会迅速导致 HCC 中 RAF 二聚化和 ERK 激活，这有助于治疗逃避。RAF 二聚体和 ERK 信号的转导激活促进 HCC 细胞存活，通过下调 BIM 防止细胞凋亡，并通过 MAPK/NF-κB 依赖性 PD-L1 基因表达激活实现免疫抑制。为了克服治疗逃避并减少全身效应，我们开发了 CXCR4 靶向纳米颗粒，将索拉非尼与 MEK 抑制剂 AZD6244 共递送至 HCC 中。通过这种方法，我们优先和有效地使 RAF/ERK 失活，上调 BIM，下调 PD-L1 在 HCC 中的表达，并促进细胞毒性 CD8+T 细胞在肿瘤内的浸润。这些作用导致肿瘤生长明显延迟。因此，这种选择性靶向肿瘤并防止反常 ERK 激活的纳米递药策略可以提高双重 RAF/MEK 抑制克服 HCC 中索拉非尼治疗逃逸的可行性。
