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Overcoming sorafenib evasion in hepatocellular carcinoma using CXCR4-targeted nanoparticles to co-deliver MEK-inhibitors.

Scientific reports (2017-03-10)
Yunching Chen, Ya-Chi Liu, Yun-Chieh Sung, Rakesh R Ramjiawan, Ts-Ting Lin, Chih-Chun Chang, Kuo-Shyang Jeng, Chiung-Fang Chang, Chun-Hung Liu, Dong-Yu Gao, Fu-Fei Hsu, Annique M Duyverman, Shuji Kitahara, Peigen Huang, Simona Dima, Irinel Popescu, Keith T Flaherty, Andrew X Zhu, Nabeel Bardeesy, Rakesh K Jain, Cyril H Benes, Dan G Duda
ABSTRACT

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.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
1,2-Dioleoyl-sn-glycero-3-phosphocholine, lyophilized powder
Sigma-Aldrich
MISSION® esiRNA, targeting human MAPK3