title: Overcoming sorafenib evasion in hepatocellular carcinoma using CXCR4-targeted nanoparticles to co-deliver MEK-inhibitors.
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.
authors.affiliation: 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.
authors.forename: Yunching
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Institute of Biomedical Engineering, National Tsing Hua University, Hsinchu, Taiwan.
authors.forename: Ya-Chi
authors.initials: YC
authors.lastname: Liu
authors.affiliation: Institute of Biomedical Engineering, National Tsing Hua University, Hsinchu, Taiwan.
authors.forename: Yun-Chieh
authors.initials: YC
authors.lastname: Sung
authors.affiliation: Steele Laboratories for Tumor Biology, Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, USA.|Angiogenesis Laboratory, Department of Medical Oncology, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: Rakesh R
authors.initials: RR
authors.lastname: Ramjiawan
authors.affiliation: Institute of Biomedical Engineering, National Tsing Hua University, Hsinchu, Taiwan.
authors.forename: Ts-Ting
authors.initials: TT
authors.lastname: Lin
authors.affiliation: Institute of Biomedical Engineering, National Tsing Hua University, Hsinchu, Taiwan.
authors.forename: Chih-Chun
authors.initials: CC
authors.lastname: Chang
authors.affiliation: Department of Surgery, Far Eastern Memorial Hospital, New Taipei City, Taiwan.
authors.forename: Kuo-Shyang
authors.initials: KS
authors.lastname: Jeng
authors.affiliation: Department of Surgery, Far Eastern Memorial Hospital, New Taipei City, Taiwan.
authors.forename: Chiung-Fang
authors.initials: CF
authors.lastname: Chang
authors.affiliation: Institute of Biomedical Engineering, National Tsing Hua University, Hsinchu, Taiwan.
authors.forename: Chun-Hung
authors.initials: CH
authors.lastname: Liu
authors.affiliation: Institute of Biomedical Engineering, National Tsing Hua University, Hsinchu, Taiwan.
authors.forename: Dong-Yu
authors.initials: DY
authors.lastname: Gao
authors.affiliation: Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan.
authors.forename: Fu-Fei
authors.initials: FF
authors.lastname: Hsu
authors.affiliation: Steele Laboratories for Tumor Biology, Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, USA.|University Medical Center, Utrecht, The Netherlands.
authors.forename: Annique M
authors.initials: AM
authors.lastname: Duyverman
authors.affiliation: Steele Laboratories for Tumor Biology, Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, USA.
authors.forename: Shuji
authors.initials: S
authors.lastname: Kitahara
authors.affiliation: Steele Laboratories for Tumor Biology, Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, USA.
authors.forename: Peigen
authors.initials: P
authors.lastname: Huang
authors.affiliation: Dan Setlacec Center of General Surgery and Liver Transplantation, Fundeni Clinical Institute, Bucharest, Romania.
authors.forename: Simona
authors.initials: S
authors.lastname: Dima
authors.affiliation: Dan Setlacec Center of General Surgery and Liver Transplantation, Fundeni Clinical Institute, Bucharest, Romania.
authors.forename: Irinel
authors.initials: I
authors.lastname: Popescu
authors.affiliation: Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, USA.
authors.forename: Keith T
authors.initials: KT
authors.lastname: Flaherty
authors.affiliation: Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, USA.
authors.forename: Andrew X
authors.initials: AX
authors.lastname: Zhu
authors.affiliation: Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, USA.
authors.forename: Nabeel
authors.initials: N
authors.lastname: Bardeesy
authors.affiliation: Steele Laboratories for Tumor Biology, Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, USA.
authors.forename: Rakesh K
authors.initials: RK
authors.lastname: Jain
authors.affiliation: Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, USA.
authors.forename: Cyril H
authors.initials: CH
authors.lastname: Benes
authors.affiliation: Steele Laboratories for Tumor Biology, Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, USA.
authors.forename: Dan G
authors.initials: DG
authors.lastname: Duda
mesh_terms: D000818:Animals; D001562:Benzimidazoles / Q000493:pharmacokinetics / Q000494:pharmacology; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D002460:Cell Line; D016503:Drug Delivery Systems / Q000379:methods*; D006801:Humans; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D051379:Mice; D053758:Nanoparticles / Q000627:therapeutic use*; D009363:Neoplasm Proteins / Q000276:immunology*; D009536:Niacinamide / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology; D010671:Phenylurea Compounds / Q000493:pharmacokinetics / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000493:pharmacokinetics / Q000494:pharmacology; D019718:Receptors, CXCR4 / Q000276:immunology*; D000077157:Sorafenib
chemical_list: C517975:AZD 6244; D001562:Benzimidazoles; C527276:CXCR4 protein, human; C514936:CXCR4 protein, mouse; D009363:Neoplasm Proteins; D010671:Phenylurea Compounds; D047428:Protein Kinase Inhibitors; D019718:Receptors, CXCR4; D009536:Niacinamide; D000077157:Sorafenib