Sorafenib for hepatocellular carcinoma: potential molecular targets and resistance mechanisms

References

• Wallace MC, Preen D, Jeffrey GP, et al. The evolving epidemiology of hepatocellular carcinoma: a global perspective. Expert Rev Gastroenterol Hepatol. 2015;9(6):765–779.
   PubMed Web of Science ®Google Scholar
• U.S. Department of Health and Human Services, National Institutes of Health, National Cancer Institute, drugs approved for liver cancer. Available at: https://www.cancer.gov/about-cancer/treatment/drugs/liver. Accessed on 14 Aug, 2020.
   Google Scholar
• Nakano M, Tanaka M, Kuromatsu R, et al. Sorafenib for the treatment of advanced hepatocellular carcinoma with extrahepatic metastasis: a prospective multicenter cohort study. Cancer Med. 2015;4(12):1836–1843.
   PubMed Web of Science ®Google Scholar
• Mao WF, Shao MH, Gao PT, et al. The important roles of RET, VEGFR2 and the RAF/MEK/ERK pathway in cancer treatment with sorafenib. Acta Pharmacol Sin. 2012;33(10):1311–1318.
   PubMed Web of Science ®Google Scholar
• Zhang JY, He B, Qu W, et al. Preparation of the albumin nanoparticle system loaded with both paclitaxel and sorafenib and its evaluation in vitro and in vivo. J Microencapsul. 2011;28(6):528–536.
   PubMed Web of Science ®Google Scholar
• Barbara JE, Kazmi F, Parkinson A, et al. Metabolism-dependent inhibition of CYP3A4 by lapatinib: evidence for formation of a metabolic intermediate complex with a nitroso/oxime metabolite formed via a nitrone intermediate. Drug Metab Dispos. 2013;41(5):1012–1022.
   PubMed Web of Science ®Google Scholar
• Food and Drug Administration. Sorafenib (Nexavar) prescribing information. [cited 2020 Jun 14]. Available from: https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/021923s020lbl.pdf.
   Google Scholar
• Edginton AN, Zimmerman EI, Vasilyeva A, et al. Sorafenib metabolism, transport, and enterohepatic recycling: physiologically based modeling and simulation in mice. Cancer Chemother Pharmacol. 2016;77(5):1039–1052.
   PubMed Web of Science ®Google Scholar
• Camidge DR, Pao W, Sequist LV. Acquired resistance to TKIs in solid tumours: learning from lung cancer. Nat Rev Clin Oncol. 2014;11(8):473–481.
   PubMed Web of Science ®Google Scholar
• Berhane S, Fox R, Garcia-Finana M, et al. Using prognostic and predictive clinical features to make personalised survival prediction in advanced hepatocellular carcinoma patients undergoing sorafenib treatment. Br J Cancer. 2019;121(2):117–124.
   PubMed Web of Science ®Google Scholar
• Zhu YJ, Zheng B, Wang HY, et al. New knowledge of the mechanisms of sorafenib resistance in liver cancer. Acta Pharmacol Sin. 2017;38(5):614–622.
   PubMed Web of Science ®Google Scholar
• Zhou TY, Zhuang LH, Hu Y, et al. Inactivation of hypoxia-induced YAP by statins overcomes hypoxic resistance tosorafenib in hepatocellular carcinoma cells. Sci Rep. 2016;6:30483.
   PubMed Web of Science ®Google Scholar
• Tang W, Chen Z, Zhang W, et al. The mechanisms of sorafenib resistance in hepatocellular carcinoma: theoretical basis and therapeutic aspects. Signal Transduct Target Ther. 2020;5(1):87.
   PubMed Web of Science ®Google Scholar
• Geier A, Macias RI, Bettinger D, et al. The lack of the organic cation transporter OCT1 at the plasma membrane of tumor cells precludes a positive response to sorafenib in patients with hepatocellular carcinoma. Oncotarget. 2017;8(9):15846–15857.
   PubMedGoogle Scholar
• Herraez E, Lozano E, Macias RI, et al. Expression of SLC22A1 variants may affect the response of hepatocellular carcinoma and cholangiocarcinoma to sorafenib. Hepatology. 2013;58(3):1065–1073.
   PubMed Web of Science ®Google Scholar
• Marin JJG, Macias RIR, Monte MJ, et al. Molecular bases of drug resistance in hepatocellular carcinoma. Cancers (Basel). 2020;12(6):1663.
   PubMed Web of Science ®Google Scholar
• Frede J, Greulich P, Nagy T, et al. A single dividing cell population with imbalanced fate drives oesophageal tumour growth. Nat Cell Biol. 2016;18(9):967–978.
   PubMed Web of Science ®Google Scholar
• Seitz T, Freese K, Dietrich P, et al. Fibroblast growth factor 9 is expressed by activated hepatic stellate cells and promotes progression of hepatocellular carcinoma. Sci Rep. 2020;10(1):4546.
   PubMed Web of Science ®Google Scholar
• Chakraborty S, Balan M, Flynn E, et al. Activation of c-Met in cancer cells mediates growth-promoting signals against oxidative stress through Nrf2-HO-1. Oncogenesis. 2019;8(2):7.
   PubMedGoogle Scholar
• Niture S, Gyamfi MA, Lin M, et al. TNFAIP8 regulates autophagy, cell steatosis, and promotes hepatocellular carcinoma cell proliferation. Cell Death Dis. 2020;11(3):178.
   PubMed Web of Science ®Google Scholar
• Lin X, Li AM, Li YH, et al. Silencing MYH9 blocks HBx-induced GSK3β ubiquitination and degradation to inhibit tumor stemness in hepatocellular carcinoma. Signal Transduct Target Ther. 2020;5(1):13.
   PubMed Web of Science ®Google Scholar
• Yin F, Feng F, Wang L, et al. SREBP-1 inhibitor betulin enhances the antitumor effect of Sorafenib on hepatocellular carcinoma via restricting cellular glycolytic activity. Cell Death Dis. 2019;10(9):672.
   PubMedGoogle Scholar
• Ma X, Qiu Y, Sun Y, et al. NOD2 inhibits tumorigenesis and increases chemosensitivity of hepatocellular carcinoma by targeting AMPK pathway. Cell Death Dis. 2020;11(3):174.
   PubMed Web of Science ®Google Scholar
• Chen YL, Zhang X, Bai J, et al. Sorafenib ameliorates bleomycin-induced pulmonary fibrosis: potential roles in the inhibition of epithelial-mesenchymal transition and fibroblast activation. Cell Death Dis. 2013;4:e665.
   PubMed Web of Science ®Google Scholar
• Sonntag R, Gassler N, Bangen JM, et al. Pro-apoptotic sorafenib signaling in murine hepatocytes depends on malignancy and is associated with PUMA expression in vitro and in vivo. Cell Death Dis. 2014;5:e1030.
   PubMed Web of Science ®Google Scholar
• Llovet JM, Villanueva A, Lachenmayer A, et al. Advances in targeted therapies for hepatocellular carcinoma in the genomic era. Nat Rev Clin Oncol. 2015;12(7):408–424.
   PubMed Web of Science ®Google Scholar
• Llovet JM, Montal R, Sia D, et al. Molecular therapies and precision medicine for hepatocellular carcinoma. Nat Rev Clin Oncol. 2018;15(10):599–616.
   PubMed Web of Science ®Google Scholar
• Ju HQ, Zhan G, Huang A, et al. ITD mutation in FLT3 tyrosine kinase promotes Warburg effect and renders therapeutic sensitivity to glycolytic inhibition. Leukemia. 2017;31(10):2143–2150.
   PubMed Web of Science ®Google Scholar
• Auclair D, Miller D, Yatsula V, et al. Antitumor activity of sorafenib in FLT3-driven leukemic cells. Leukemia. 2007;21(3):439–445.
   PubMed Web of Science ®Google Scholar
• Li S, Wu L, Feng J, et al. In vitro and in vivo study of epigallocatechin-3-gallate-induced apoptosis in aerobic glycolytic hepatocellular carcinoma cells involving inhibition of phosphofructokinase activity. Sci Rep. 2016;6:28479.
   PubMed Web of Science ®Google Scholar
• Metzelder SK, Michel C, von-Bonin M, et al. NFATc1 as a therapeutic target in FLT3-ITD-positive AML. Leukemia. 2015;29(7):1470–1477.
   PubMed Web of Science ®Google Scholar
• Sohn BH, Park IY, Shin JH, et al. Glutamine synthetase mediates sorafenib sensitivity in β-catenin-active hepatocellular carcinoma cells. Exp Mol Med. 2018;50(1):e421.
   PubMedGoogle Scholar
• Yoon S, Lee EJ, Choi JH, et al. Recapitulation of pharmacogenomic data reveals that invalidation of SULF2 enhance sorafenib susceptibility in liver cancer. Oncogene. 2018;37(32):4443–4454.
   PubMed Web of Science ®Google Scholar
• Feng F, Jiang Q, Cao S, et al. Pregnane X receptor mediates sorafenib resistance in advanced hepatocellular carcinoma. Biochim Biophys Acta Gen Subj. 2018;1862(4):1017–1030.
   PubMed Web of Science ®Google Scholar
• Noeparast A, Giron P, Noor A, et al. CRAF mutations in lung cancer can be oncogenic and predict sensitivity to combined type II RAF and MEK inhibition. Oncogene. 2019;38(31):5933–5941.
   PubMed Web of Science ®Google Scholar
• Xu J, Zheng L, Chen J, et al. Increasing AR by HIF-2α inhibitor (PT-2385) overcomes the side-effects of sorafenib by suppressing hepatocellular carcinoma invasion via alteration of pSTAT3, pAKT and pERK signals. Cell Death Dis. 2017;8(10):e3095.
   PubMedGoogle Scholar
• Fan LC, Shiau CW, Tai WT, et al. SHP-1 is a negative regulator of epithelial-mesenchymal transition in hepatocellular carcinoma. Oncogene. 2015;34(41):5252–5263.
   PubMed Web of Science ®Google Scholar
• Su TH, Shiau CW, Jao P, et al. Src-homology protein tyrosine phosphatase-1 agonist, SC-43, reduces liver fibrosis. Sci Rep. 2017;7(1):1728.
   PubMedGoogle Scholar
• Wei JC, Meng FD, Qu K, et al. Sorafenib inhibits proliferation and invasion of human hepatocellular carcinoma cells via up-regulation of p53 and suppressing FoxM1. Acta Pharmacol Sin. 2015;36(2):241–251.
   PubMed Web of Science ®Google Scholar
• Zhang PF, Li KS, Shen YH, et al. Galectin-1 induces hepatocellular carcinoma EMT and sorafenib resistance by activating FAK/PI3K/AKT signaling. Cell Death Dis. 2016;7:e2201.
   PubMed Web of Science ®Google Scholar
• Emma MR, Iovanna JL, Bachvarov D, et al. NUPR1, a new target in liver cancer: implication in controlling cell growth, migration, invasion and sorafenib resistance. Cell Death Dis. 2016;7(6):e2269.
   PubMedGoogle Scholar
• Chen Y, Liu YC, Sung YC, et al. Overcoming sorafenib evasion in hepatocellular carcinoma using CXCR4-targeted nanoparticles to co-deliver MEK-inhibitors. Sci Rep. 2017;7:44123.
   PubMed Web of Science ®Google Scholar
• Zhang W, Konopleva M, Ruvolo VR, et al. Sorafenib induces apoptosis of AML cells via Bim-mediated activation of the intrinsic apoptotic pathway. Leukemia. 2008;22(4):808–818.
   PubMed Web of Science ®Google Scholar
• Cao T, Jiang N, Liao H, et al. The FLT3-ITD mutation and the expression of its downstream signaling intermediates STAT5 and Pim-1 are positively correlated with CXCR4 expression in patients with acute myeloid leukemia. Sci Rep. 2019;9(1):12209.
   PubMedGoogle Scholar
• Haga Y, Kanda T, Nakamura M, et al. Overexpression of c-Jun contributes to sorafenib resistance in human hepatoma cell lines. PLoS One. 2017;12(3):e0174153.
   PubMed Web of Science ®Google Scholar
• Sasaki R, Kanda T, Fujisawa M, et al. Different mechanisms of action of regorafenib and lenvatinib on toll-like receptor-signaling pathways in human hepatoma cell lines. Int J Mol Sci. 2020;21(9):3349.
   Web of Science ®Google Scholar
• Hagiwara S, Kudo M, Nagai T, et al. Activation of JNK and high expression level of CD133 predict a poor response to sorafenib in hepatocellular carcinoma. Br J Cancer. 2012;106(12):1997–2003.
   PubMed Web of Science ®Google Scholar
• Chen W, Xiao W, Zhang K, et al. Activation of c-Jun predicts a poor response to sorafenib in hepatocellular carcinoma: preliminary clinical evidence. Sci Rep. 2016;6:22976.
   PubMed Web of Science ®Google Scholar
• Xu Z, Yang F, Wei D, et al. Long noncoding RNA-SRLR elicits intrinsic sorafenib resistance via evoking IL-6/STAT3 axis in renal cell carcinoma. Oncogene. 2017;36(14):1965–1977.
   PubMed Web of Science ®Google Scholar
• Yuen JS, Sim MY, Siml HG, et al. Inhibition of angiogenic and non-angiogenic targets by sorafenib in renal cell carcinoma (RCC) in a RCC xenograft model. Br J Cancer. 2011;104(6):941–947.
   PubMed Web of Science ®Google Scholar
• Mendez-Blanco C, Fondevila F, Garcia-Palomo A, et al. Sorafenib resistance in hepatocarcinoma: role of hypoxia-inducible factors. Exp Mol Med. 2018;50(10):1–9.
   PubMedGoogle Scholar
• Lam W, Jiang Z, Guan F, et al. PHY906(KD018), an adjuvant based on a 1800-year-old Chinese medicine, enhanced the anti-tumor activity of sorafenib by changing the tumor microenvironment. Sci Rep. 2015;5:9384.
   PubMed Web of Science ®Google Scholar
• Mendez-Blanco C, Fernandez-Palanca P, Fondevila F, et al. Prognostic and clinicopathological significance of hypoxia-inducible factors 1α and 2α in hepatocellular carcinoma: a systematic review with meta-analysis. Ther Adv Med Oncol. 2021;13:1758835920987071.
   Web of Science ®Google Scholar
• Ding ZN, Dong ZR, Chen ZQ, et al. Effects of hypoxia-inducible factor-1α and hypoxia-inducible factor-2α overexpression on hepatocellular carcinoma survival: a systematic review with meta-analysis. J Gastroenterol Hepatol. 2021;36(6):1487–1496.
   PubMed Web of Science ®Google Scholar
• Martens S, Jeong M, Tonnus W, et al. Sorafenib tosylate inhibits directly necrosome complex formation and protects in mouse models of inflammation and tissue injury. Cell Death Dis. 2017;8(6):e2904.
   PubMedGoogle Scholar
• Quintavalle C, Hindupur SK, Quagliata L, et al. Phosphoprotein enriched in diabetes (PED/PEA15) promotes migration in hepatocellular carcinoma and confers resistance to sorafenib. Cell Death Dis. 2017;8(10):e3138.
   PubMedGoogle Scholar
• Chen CT, Liao LZ, Lu CH, et al. Quantitative phosphoproteomic analysis identifies the potential therapeutic target EphA2 for overcoming sorafenib resistance in hepatocellular carcinoma cells. Exp Mol Med. 2020;52(3):497–513.
   PubMed Web of Science ®Google Scholar
• Dong MP, Enomoto M, Thuy LTT, et al. Clinical significance of circulating soluble immune checkpoint proteins in sorafenib-treated patients with advanced hepatocellular carcinoma. Sci Rep. 2020;10(1):3392.
   PubMed Web of Science ®Google Scholar
• Raoul JL, Kudo M, Finn RS, et al. Systemic therapy for intermediate and advanced hepatocellular carcinoma: Sorafenib and beyond. Cancer Treat Rev. 2018;68:16–24.
   PubMed Web of Science ®Google Scholar
• Eicher C, Dewerth A, Thomale J, et al. Effect of sorafenib combined with cytostatic agents on hepatoblastoma cell lines and xenografts. Br J Cancer. 2013;108(2):334–341.
   PubMed Web of Science ®Google Scholar
• Shen YC, Ou DL, Hsu C, et al. Activating oxidative phosphorylation by a pyruvate dehydrogenase kinase inhibitor overcomes sorafenib resistance of hepatocellular carcinoma. Br J Cancer. 2013;108(1):72–81.
   PubMed Web of Science ®Google Scholar
• Wan J, Liu T, Mei L, et al. Synergistic antitumour activity of sorafenib in combination with tetrandrine is mediated by reactive oxygen species (ROS)/Akt signaling. Br J Cancer. 2013;109(2):342–350.
   PubMed Web of Science ®Google Scholar
• Rosa R, Damiano V, Nappi L, et al. Angiogenic and signalling proteins correlate with sensitivity to sequential treatment in renal cell cancer. Br J Cancer. 2013;109(3):686–693.
   PubMed Web of Science ®Google Scholar
• Ma X, Wang L, Li H, et al. Predictive immunohistochemical markers related to drug selection for patients treated with sunitinib or sorafenib for metastatic renal cell cancer. Sci Rep. 2016;6:30886.
   PubMed Web of Science ®Google Scholar
• Fondevila F, Mendez-Blanco C, Fernandez-Palanca P, et al. Anti-tumoral activity of single and combined regorafenib treatments in preclinical models of liver and gastrointestinal cancers. Exp Mol Med. 2019;51(9):1–15.
   PubMedGoogle Scholar
• Zhang SS, Ni YH, Zhao CR, et al. Capsaicin enhances the antitumor activity of sorafenib in hepatocellular carcinoma cells and mouse xenograft tumors through increased ERK signaling. Acta Pharmacol Sin. 2018;39(3):438–448.
   PubMed Web of Science ®Google Scholar
• Gavini J, Dommann N, Jakob MO, et al. Verteporfin-induced lysosomal compartment dysregulation potentiates the effect of sorafenib in hepatocellular carcinoma. Cell Death Dis. 2019;10(10):749.
   PubMedGoogle Scholar
• Locatelli SL, Giacomini A, Guidetti A, et al. Perifosine and sorafenib combination induces mitochondrial cell death and antitumor effects in NOD/SCID mice with Hodgkin lymphoma cell line xenografts. Leukemia. 2013;27(8):1677–1687.
   PubMed Web of Science ®Google Scholar
• Liang Q, Kong L, Du Y, et al. Antitumorigenic and antiangiogenic efficacy of apatinib in liver cancer evaluated by multimodality molecular imaging. Exp Mol Med. 2019;51(7):1–11.
   Google Scholar
• Ye L, Mayerle J, Ziesch A, et al. The PI3K inhibitor copanlisib synergizes with sorafenib to induce cell death in hepatocellular carcinoma. Cell Death Discov. 2019;5:86.
   PubMed Web of Science ®Google Scholar
• Lindblad O, Cordero E, Puissant A, et al. Aberrant activation of the PI3K/mTOR pathway promotes resistance to sorafenib in AML. Oncogene. 2016;35(39):5119–5131.
   PubMed Web of Science ®Google Scholar
• Palmer DH, Ma YT, Peck-Radosavljevic M, et al. A multicentre, open-label, phase-I/randomised phase-II study to evaluate safety, pharmacokinetics, and efficacy of nintedanib vs. sorafenib in European patients with advanced hepatocellular carcinoma. Br J Cancer. 2018;118(9):1162–1168.
   PubMed Web of Science ®Google Scholar
• Assenat E, Pageaux GP, Thezenas S, et al. Sorafenib alone vs. sorafenib plus GEMOX as 1st-line treatment for advanced HCC: the phase II randomised PRODIGE 10 trial. Br J Cancer. 2019;120(9):896–902.
   PubMed Web of Science ®Google Scholar
• Abdelmageed MM, El-Naga RN, El-Demerdash E, et al. Indole-3- carbinol enhances sorafenib cytotoxicity in hepatocellular carcinoma cells: a mechanistic study. Sci Rep. 2016;6(1):32733.
   PubMedGoogle Scholar
• Quintela-Fandino M, Krzyzanowska M, Duncan G, et al. In vivo RAF signal transduction as a potential biomarker for sorafenib efficacy in patients with neuroendocrine tumours. Br J Cancer. 2013;108(6):1298–1305.
   PubMed Web of Science ®Google Scholar
• Wu WD, Chen PS, Omar HA, et al. Antrodia cinnamomea boosts the anti-tumor activity of sorafenib in xenograft models of human hepatocellular carcinoma. Sci Rep. 2018;8(1):12914.
   PubMedGoogle Scholar
• Xia H, Lee KW, Chen J, et al. Simultaneous silencing of ACSL4 and induction of GADD45B in hepatocellular carcinoma cells amplifies the synergistic therapeutic effect of aspirin and sorafenib. Cell Death Discov. 2017;3:17058.
   PubMed Web of Science ®Google Scholar
• Hsu FT, Chang B, Chen JC, et al. Synergistic effect of sorafenib and radiation on human oral carcinoma in vivo. Sci Rep. 2015;5:15391.
   PubMed Web of Science ®Google Scholar
• Samalin E, Bouche O, Thezenas S, et al. Sorafenib and irinotecan (NEXIRI) as second- or later-line treatment for patients with metastatic colorectal cancer and KRAS-mutated tumours: a multicentre phase I/II trial. Br J Cancer. 2014;110(5):1148–1154.
   PubMed Web of Science ®Google Scholar
• Zhang L, Li S, Wang R, et al. Cytokine augments the sorafenib-induced apoptosis in Huh7 liver cancer cell by inducing mitochondrial fragmentation and activating MAPK-JNK signalling pathway. Biomed Pharmacother. 2019;110:213–223.
   PubMed Web of Science ®Google Scholar
• Pollutri D, Patrizi C, Marinelli S, et al. The epigenetically regulated miR-494 associates with stem-cell phenotype and induces sorafenib resistance in hepatocellular carcinoma. Cell Death Dis. 2018;9(1):4.
   PubMedGoogle Scholar
• Rudalska R, Dauch D, Longerich T, et al. In vivo RNAi screening identifies a mechanism of sorafenib resistance in liver cancer. Nat Med. 2014;20(10):1138–1146.
   PubMed Web of Science ®Google Scholar
• Sun W, He B, Yang B, et al. Genome-wide CRISPR screen reveals SGOL1 as a druggable target of sorafenib-treated hepatocellular carcinoma. Lab Invest. 2018;98(6):734–744.
   PubMed Web of Science ®Google Scholar
• Wei L, Lee D, Law CT, et al. Genome-wide CRISPR/Cas9 library screening identified PHGDH as a critical driver for sorafenib resistance in HCC. Nat Commun. 2019;10(1):4681.
   PubMedGoogle Scholar
• Qiu Y, Shan W, Yang Y, et al. Reversal of sorafenib resistance in hepatocellular carcinoma: epigenetically regulated disruption of 14-3-3η/hypoxia-inducible factor-1α. Cell Death Discov. 2019;5:120.
   PubMed Web of Science ®Google Scholar
• Awan FM, Naz A, Obaid A, et al. MicroRNA pharmacogenomics based integrated model of miR-17-92 cluster in sorafenib resistant HCC cells reveals a strategy to forestall drug resistance. Sci Rep. 2017;7(1):11448.
   PubMedGoogle Scholar
• Faranda T, Grossi I, Manganelli M, et al. Differential expression profiling of long non-coding RNA GAS5 and miR-126-3p in human cancer cells in response to sorafenib. Sci Rep. 2019;9(1):9118.
   PubMedGoogle Scholar
• Yoshida M, Yamashita T, Okada H, et al. Sorafenib suppresses extrahepatic metastasis de novo in hepatocellular carcinoma through inhibition of mesenchymal cancer stem cells characterized by the expression of CD90. Sci Rep. 2017;7(1):11292.
   PubMedGoogle Scholar
• Song Y, Lee SY, Kim S, et al. Inhibitors of Na+/K+ ATPase exhibit antitumor effects on multicellular tumor spheroids of hepatocellular carcinoma. Sci Rep. 2020;10(1):5318.
   PubMed Web of Science ®Google Scholar
• Eilenberger C, Rothbauer M, Ehmoser EK, et al. Effect of spheroidal age on sorafenib diffusivity and toxicity in a 3D HepG2 spheroid model. Sci Rep. 2019;9(1):4863.
   PubMedGoogle Scholar
• Kususda Y, Miyake H, Gleave ME, et al. Clusterin inhibition using OGX-011 synergistically enhances antitumour activity of sorafenib in a human renal cell carcinoma model. Br J Cancer. 2012;106(12):1945–1952.
   PubMed Web of Science ®Google Scholar
• Bao Y, Yang F, Liu B, et al. Angiopoietin-like protein 3 blocks nuclear import of FAK and contributes to sorafenib response. Br J Cancer. 2018;119(4):450–461.
   PubMed Web of Science ®Google Scholar
• Pinato DJ, Brown MW, Trousil S, et al. Integrated analysis of multiple receptor tyrosine kinases identifies Axl as a therapeutic target and mediator of resistance to sorafenib in hepatocellular carcinoma. Br J Cancer. 2019;120(5):512–521.
   PubMed Web of Science ®Google Scholar
• Zhang K, Chen J, Zhou H, et al. PU.1/microRNA-142-3p targets ATG5/ATG16L1 to inactivate autophagy and sensitize hepatocellular carcinoma cells to sorafenib. Cell Death Dis. 2018;9(3):312.
   PubMedGoogle Scholar
• Dong N, Shi X, Wang S, et al. M2 macrophages mediate sorafenib resistance by secreting HGF in a feed-forward manner in hepatocellular carcinoma. Br J Cancer. 2019;121(1):22–33.
   PubMed Web of Science ®Google Scholar
• Li J, Wu PW, Zhou Y, et al. Rage induces hepatocellular carcinoma proliferation and sorafenib resistance by modulating autophagy. Cell Death Dis. 2018;9(2):225.
   PubMedGoogle Scholar
• Qin CD, Ma DN, Zhang SZ, et al. The Rho GTPase Rnd1 inhibits epithelial-mesenchymal transition in hepatocellular carcinoma and is a favorable anti-metastasis target. Cell Death Dis. 2018;9(5):486.
   PubMedGoogle Scholar
• Huo D, Zhu J, Chen G, et al. Eradication of unresectable liver metastasis through induction of tumour specific energy depletion. Nat Commun. 2019;10(1):3051.
   PubMedGoogle Scholar
• Lu S, Yao Y, Xu G, et al. CD24 regulates sorafenib resistance via activating autophagy in hepatocellular carcinoma. Cell Death Dis. 2018;9(6):646.
   PubMedGoogle Scholar
• Rodriguez-Hernandez MA, Gonzalez R, de la Rosa AJ, et al. Molecular characterization of autophagic and apoptotic signaling induced by sorafenib in liver cancer cells. J Cell Physiol. 2018;234(1):692–708.
   PubMed Web of Science ®Google Scholar
• Prieto-Dominguez N, Ordonez R, Fernandez A, et al. Modulation of autophagy by sorafenib: effects on treatment response. Front Pharmacol. 2016;7:151.
   PubMed Web of Science ®Google Scholar
• Zhang Y, Li D, Jiang Q, et al. Novel ADAM-17 inhibitor ZLDI-8 enhances the in vitro and in vivo chemotherapeutic effects of sorafenib on hepatocellular carcinoma cells. Cell Death Dis. 2018;9(7):743.
   PubMedGoogle Scholar
• Niu LL, Cheng CL, Li MY, et al. ID1-induced p16/IL6 axis activation contributes to the resistant of hepatocellular carcinoma cells to sorafenib. Cell Death Dis. 2018;9(9):852.
   PubMedGoogle Scholar
• Jiang W, Li G, Li W, et al. Sodium orthovanadate overcomes sorafenib resistance of hepatocellular carcinoma cells by inhibiting Na+/K+-ATPase activity and hypoxia-inducible pathways. Sci Rep. 2018;8(1):9706.
   PubMedGoogle Scholar
• Enomoto H, Tao L, Eguchi R, et al. The in vivo antitumor effects of type I-interferon against hepatocellular carcinoma: the suppression of tumor cell growth and angiogenesis. Sci Rep. 2017;7(1):12189.
   PubMedGoogle Scholar
• Escudier B, Michaelson MD, Motzer RJ, et al. Axitinib versus sorafenib in advanced renal cell carcinoma: subanalyses by prior therapy from a randomised phase III trial. Br J Cancer. 2014;110(12):2821–2828.
   PubMed Web of Science ®Google Scholar
• Procopio G, Bellmunt J, Dutcher J, et al. Sorafenib tolerability in elderly patients with advanced renal cell carcinoma: results from a large pooled analysis. Br J Cancer. 2013;108(2):311–318.
   PubMed Web of Science ®Google Scholar
• Funakoshi T, Latif A, Galsky MD. Risk of hypertension in cancer patients treated with sorafenib: an updated systematic review and meta-analysis. J Hum Hypertens. 2013;27(10):601–611.
   PubMed Web of Science ®Google Scholar
• Hennenberg M, Trebicka J, Kohistani Z, et al. Hepatic and HSC-specific sorafenib effects in rats with established secondary biliary cirrhosis. Lab Invest. 2011;91(2):241–251.
   PubMed Web of Science ®Google Scholar
• Caiola E, Frapolli R, Tomanelli M, et al. Wee1 inhibitor MK1775 sensitizes KRAS mutated NSCLC cells to Sorafenib. Sci Rep. 2018;8(1):948.
   PubMedGoogle Scholar
• Dahlmanns M, Yakubov E, Chen D, et al. Chemotherapeutic xCT inhibitors sorafenib and erastin unraveled with the synaptic optogenetic function analysis tool. Cell Death Discov. 2017;3:17030.
   PubMed Web of Science ®Google Scholar
• Antar A, Otrock ZK, El-Cheikh J, et al. Inhibition of FLT3 in AML: a focus on sorafenib. Bone Marrow Transplant. 2017;52(3):344–351.
   PubMed Web of Science ®Google Scholar
• Zhao X, Tian C, Puszyk WM, et al. OPA1 downregulation is involved in sorafenib-induced apoptosis in hepatocellular carcinoma. Lab Invest. 2013;93(1):8–19.
   PubMed Web of Science ®Google Scholar
• Kharaziha P, Rodriguez P, Li Q, et al. Targeting of distinct signaling cascades and cancer-associated fibroblasts define the efficacy of sorafenib against prostate cancer cells. Cell Death Dis. 2012;3:e262.
   PubMed Web of Science ®Google Scholar
• Bazzola L, Foroni C, Andreis D, et al. Combination of letrozole, metronomic cyclophosphamide and sorafenib is well-tolerated and shows activity in patients with primary breast cancer. Br J Cancer. 2015;112(1):52–60.
   PubMed Web of Science ®Google Scholar
• Laurent S, Saei AA, Behzadi S, et al. Superparamagnetic iron oxide nanoparticles for delivery of therapeutic agents: opportunities and challenges. Expert Opin Drug Deliv. 2014;11(9):1449–1470.
   PubMed Web of Science ®Google Scholar
• Louguet S, Rousseau B, Epherre R, et al. Thermoresponsive polymer brush-functionalized magnetic manganite nanoparticles for remotely triggered drug release. Polym Chem. 2012;3(6):1408–1417.
   Web of Science ®Google Scholar
• Heidarinasab A, Panahi HA, Faramarzi M, et al. Synthesis of thermosensitive magnetic nanocarrier for controlled sorafenib delivery. Mater Sci Eng C Mater Biol Appl. 2016;67:42–50.
   PubMed Web of Science ®Google Scholar
• Tom G, Philip S, Isaac R, et al. Preparation of an efficient and safe polymeric-magnetic nanoparticle delivery system for sorafenib in hepatocellular carcinoma. Life Sci. 2018;206:10–21.
   PubMed Web of Science ®Google Scholar
• Li YJ, Dong M, Kong FM, et al. Folate-decorated anticancer drug and magnetic nanoparticles encapsulated polymeric carrier for liver cancer therapeutics. Int J Pharm. 2015;489(1-2):83–90.
   PubMedGoogle Scholar