キタハラ　シユウジ   Kitahara Shiyuuji   北原　秀治    所属   医学研究科 医学研究科 (医学部医学科をご参照ください)    職種   特任准教授
論文種別	原著
言語種別	英語
査読の有無	査読あり
表題	Overcoming sorafenib evasion in hepatocellular carcinoma using CXCR4-targeted nanoparticles to co-deliver MEK-inhibitors.
掲載誌名	正式名：Scientific reports 略　 称：Sci Rep ISSNコード：(2045-2322)2045-2322(Linking)
掲載区分	国外
巻・号・頁	7,pp.44123
著者・共著者	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
発行年月	2017/03
概要	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