KITAHARA Shuji
   Department   Research Institutes and Facilities, Research Institutes and Facilities
   Position   Associate Professor (Fixed Term)
Article types Original article
Language English
Peer review Peer reviewed
Title Overcoming sorafenib evasion in hepatocellular carcinoma using CXCR4-targeted nanoparticles to co-deliver MEK-inhibitors.
Journal Formal name：Scientific reports
Abbreviation：Sci Rep
ISSN code：(2045-2322)2045-2322(Linking)
Domestic / ForeginForegin
Volume, Issue, Page 7,pp.44123
Author and coauthor Chen Yunching, Liu Ya-Chi, Sung Yun-Chieh, Ramjiawan Rakesh R, Lin Ts-Ting, Chang Chih-Chun, Jeng Kuo-Shyang, Chang Chiung-Fang, Liu Chun-Hung, Gao Dong-Yu, Hsu Fu-Fei, Duyverman Annique M, Kitahara Shuji, Huang Peigen, Dima Simona, Popescu Irinel, Flaherty Keith T, Zhu Andrew X, Bardeesy Nabeel, Jain Rakesh K, Benes Cyril H, Duda Dan G
Publication date 2017/03
Summary 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.
DOI 10.1038/srep44123
PMID 28276530