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

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. JainCyril H. Benes, Dan G. Duda

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

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.

Original languageEnglish
Article number44123
JournalScientific Reports
Volume7
DOIs
Publication statusPublished - 9 Mar 2017

Cite this

Chen, Y., Liu, Y. C., Sung, Y. C., Ramjiawan, R. R., Lin, T. T., Chang, C. C., ... Duda, D. G. (2017). Overcoming sorafenib evasion in hepatocellular carcinoma using CXCR4-targeted nanoparticles to co-deliver MEK-inhibitors. Scientific Reports, 7, [44123]. https://doi.org/10.1038/srep44123