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Semin Liver Dis 2022; 42(01): 087-103
DOI: 10.1055/s-0041-1735631
Review Article

Mechanisms of Pharmacoresistance in Hepatocellular Carcinoma: New Drugs but Old Problems

Jose J.G. Marin
1   Experimental Hepatology and Drug Targeting (HEVEPHARM), University of Salamanca, IBSAL, Salamanca, Spain
2   Center for the Study of Liver and Gastrointestinal Diseases (CIBERehd), Carlos III National Institute of Health, Madrid, Spain
,
Marta R. Romero
1   Experimental Hepatology and Drug Targeting (HEVEPHARM), University of Salamanca, IBSAL, Salamanca, Spain
2   Center for the Study of Liver and Gastrointestinal Diseases (CIBERehd), Carlos III National Institute of Health, Madrid, Spain
,
Elisa Herraez
1   Experimental Hepatology and Drug Targeting (HEVEPHARM), University of Salamanca, IBSAL, Salamanca, Spain
2   Center for the Study of Liver and Gastrointestinal Diseases (CIBERehd), Carlos III National Institute of Health, Madrid, Spain
,
Maitane Asensio
1   Experimental Hepatology and Drug Targeting (HEVEPHARM), University of Salamanca, IBSAL, Salamanca, Spain
2   Center for the Study of Liver and Gastrointestinal Diseases (CIBERehd), Carlos III National Institute of Health, Madrid, Spain
,
Sara Ortiz-Rivero
1   Experimental Hepatology and Drug Targeting (HEVEPHARM), University of Salamanca, IBSAL, Salamanca, Spain
,
Anabel Sanchez-Martin
1   Experimental Hepatology and Drug Targeting (HEVEPHARM), University of Salamanca, IBSAL, Salamanca, Spain
,
Luca Fabris
3   Department of Molecular Medicine (DMM), University of Padua, Padua, Italy
4   Department of Internal Medicine, Yale Liver Center (YLC), School of Medicine, Yale University New Haven, Connecticut
,
Oscar Briz
1   Experimental Hepatology and Drug Targeting (HEVEPHARM), University of Salamanca, IBSAL, Salamanca, Spain
2   Center for the Study of Liver and Gastrointestinal Diseases (CIBERehd), Carlos III National Institute of Health, Madrid, Spain
› Author Affiliations Funding This study has been funded by Instituto de Salud Carlos III through the grants PI19/00819 and PI20/00189 (co-funded by European Regional Development Fund/European Social Fund “A way to make Europe”/”Investing in your future”); the CIBERehd (EHD15PI05/2016); “Junta de Castilla y Leon” (SA074P20); AECC Scientific Foundation (2017/2020), Spain; “Centro Internacional sobre el Envejecimiento” (OLD-HEPAMARKER, 0348_CIE_6_E), Spain; Fundació Marato TV3, Spain (201916–31); and “Programa de financiación de grupos de investigación. Modalidad C2,” University of Salamanca (2019–2020). S.O.-R. was supported by a postdoctoral contract from University of Salamanca funded by the “Junta de Castilla y León” and the “Fondo Social Europeo,” Spain (BDNS 505421 and EDU/1192/2020). A.S.-M. was supported by a predoctoral scholarship (FPU) funded by the Ministry of Science, Innovation and Universities, Spain. M.A. was funded by a postdoctoral contract of the CIBERehd.
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Abstract

Hepatocellular carcinoma (HCC) is a malignancy with poor prognosis when diagnosed at advanced stages in which curative treatments are no longer applicable. A small group of these patients may still benefit from transarterial chemoembolization. The only therapeutic option for most patients with advanced HCC is systemic pharmacological treatments based on tyrosine kinase inhibitors (TKIs) and immunotherapy. Available drugs only slightly increase survival, as tumor cells possess additive and synergistic mechanisms of pharmacoresistance (MPRs) prior to or enhanced during treatment. Understanding the molecular basis of MPRs is crucial to elucidate the genetic signature underlying HCC resistome. This will permit the selection of biomarkers to predict drug treatment response and identify tumor weaknesses in a personalized and dynamic way. In this article, we have reviewed the role of MPRs in current first-line drugs and the combinations of immunotherapeutic agents with novel TKIs being tested in the treatment of advanced HCC.

Keywords

immunotherapy - liver cancer - multidrug resistance - targeted therapy - TKI


Publication History

Article published online:
20 September 2021

© 2021. Thieme. All rights reserved.

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  • References

  • 1 Llovet JM, Kelley RK, Villanueva A. et al. Hepatocellular carcinoma. Nat Rev Dis Primers 2021; 7 (01) 6
    CrossrefPubMedGoogle Scholar
  • 2 Ferlay J, Colombet M, Soerjomataram I. et al. Cancer statistics for the year 2020: an overview. Int J Cancer 2021; 149: 778-789
    CrossrefPubMedGoogle Scholar
  • 3 Tsilimigras DI, Bagante F, Moris D. et al. Defining the chance of cure after resection for hepatocellular carcinoma within and beyond the Barcelona Clinic Liver Cancer guidelines: a multi-institutional analysis of 1,010 patients. Surgery 2019; 166 (06) 967-974
    CrossrefPubMedGoogle Scholar
  • 4 O'Leary C, Mahler M, Soulen MC. Curative-intent therapies in localized hepatocellular carcinoma. Curr Treat Options Oncol 2020; 21 (04) 31
    CrossrefPubMedGoogle Scholar
  • 5 Vogel A, Martinelli E. ESMO Guidelines Committee. Electronic address: clinicalguidelines@esmo.org, ESMO Guidelines Committee. Updated treatment recommendations for hepatocellular carcinoma (HCC) from the ESMO Clinical Practice Guidelines. Ann Oncol 2021; 32 (06) 801-805
    CrossrefPubMedGoogle Scholar
  • 6 Llovet JM, Real MI, Montaña X. et al; Barcelona Liver Cancer Group. Arterial embolisation or chemoembolisation versus symptomatic treatment in patients with unresectable hepatocellular carcinoma: a randomised controlled trial. Lancet 2002; 359 (9319): 1734-1739
    CrossrefPubMedGoogle Scholar
  • 7 Bruix J, Gores GJ, Mazzaferro V. Hepatocellular carcinoma: clinical frontiers and perspectives. Gut 2014; 63 (05) 844-855
    CrossrefPubMedGoogle Scholar
  • 8 Llovet JM, Ricci S, Mazzaferro V. et al; SHARP Investigators Study Group. Sorafenib in advanced hepatocellular carcinoma. N Engl J Med 2008; 359 (04) 378-390
    CrossrefPubMedGoogle Scholar
  • 9 Cheng AL, Kang YK, Chen Z. et al. Efficacy and safety of sorafenib in patients in the Asia-Pacific region with advanced hepatocellular carcinoma: a phase III randomised, double-blind, placebo-controlled trial. Lancet Oncol 2009; 10 (01) 25-34
    CrossrefPubMedGoogle Scholar
  • 10 Vogel A, Bathon M, Saborowski A. Advances in systemic therapy for the first-line treatment of unresectable HCC. Expert Rev Anticancer Ther 2021; 21 (06) 621-628
    CrossrefPubMedGoogle Scholar
  • 11 Giraud J, Chalopin D, Blanc JF, Saleh M. Hepatocellular carcinoma immune landscape and the potential of immunotherapies. Front Immunol 2021; 12: 655697
    CrossrefPubMedGoogle Scholar
  • 12 Marin JJG, Macias RIR, Monte MJ. et al. Molecular bases of drug resistance in hepatocellular carcinoma. Cancers (Basel) 2020; 12 (06) E1663
    CrossrefPubMedGoogle Scholar
  • 13 Marin JJ, Macias RI. Understanding drug resistance mechanisms in cholangiocarcinoma: assisting the clinical development of investigational drugs. Expert Opin Investig Drugs 2021; 30 (07) 675-679
    CrossrefPubMedGoogle Scholar
  • 14 Eisenhauer EA, Therasse P, Bogaerts J. et al. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer 2009; 45 (02) 228-247
    CrossrefPubMedGoogle Scholar
  • 15 Le Grazie M, Biagini MR, Tarocchi M, Polvani S, Galli A. Chemotherapy for hepatocellular carcinoma: the present and the future. World J Hepatol 2017; 9 (21) 907-920
    CrossrefPubMedGoogle Scholar
  • 16 Patt YZ, Hassan MM, Aguayo A. et al. Oral capecitabine for the treatment of hepatocellular carcinoma, cholangiocarcinoma, and gallbladder carcinoma. Cancer 2004; 101 (03) 578-586
    CrossrefPubMedGoogle Scholar
  • 17 Kaseb AO, Shindoh J, Patt YZ. et al. Modified cisplatin/interferon α-2b/doxorubicin/5-fluorouracil (PIAF) chemotherapy in patients with no hepatitis or cirrhosis is associated with improved response rate, resectability, and survival of initially unresectable hepatocellular carcinoma. Cancer 2013; 119 (18) 3334-3342
    CrossrefPubMedGoogle Scholar
  • 18 Qin S, Bai Y, Lim HY. et al. Randomized, multicenter, open-label study of oxaliplatin plus fluorouracil/leucovorin versus doxorubicin as palliative chemotherapy in patients with advanced hepatocellular carcinoma from Asia. J Clin Oncol 2013; 31 (28) 3501-3508
    CrossrefPubMedGoogle Scholar
  • 19 Zaanan A, Williet N, Hebbar M. et al. Gemcitabine plus oxaliplatin in advanced hepatocellular carcinoma: a large multicenter AGEO study. J Hepatol 2013; 58 (01) 81-88
    CrossrefPubMedGoogle Scholar
  • 20 Sieghart W, Hucke F, Peck-Radosavljevic M. Transarterial chemoembolization: modalities, indication, and patient selection. J Hepatol 2015; 62 (05) 1187-1195
    CrossrefPubMedGoogle Scholar
  • 21 Chang Y, Jeong SW, Young Jang J, Jae Kim Y. Recent updates of transarterial chemoembolilzation in hepatocellular carcinoma. Int J Mol Sci 2020; 21 (21) E8165
    CrossrefPubMedGoogle Scholar
  • 22 Lencioni R, de Baere T, Soulen MC, Rilling WS, Geschwind JF. Lipiodol transarterial chemoembolization for hepatocellular carcinoma: a systematic review of efficacy and safety data. Hepatology 2016; 64 (01) 106-116
    CrossrefPubMedGoogle Scholar
  • 23 Ikeda M, Morizane C, Ueno M, Okusaka T, Ishii H, Furuse J. Chemotherapy for hepatocellular carcinoma: current status and future perspectives. Jpn J Clin Oncol 2018; 48 (02) 103-114
    CrossrefPubMedGoogle Scholar
  • 24 Lo CM, Ngan H, Tso WK. et al. Randomized controlled trial of transarterial lipiodol chemoembolization for unresectable hepatocellular carcinoma. Hepatology 2002; 35 (05) 1164-1171
    CrossrefPubMedGoogle Scholar
  • 25 Bargellini I, Sacco R, Bozzi E. et al. Transarterial chemoembolization in very early and early-stage hepatocellular carcinoma patients excluded from curative treatment: a prospective cohort study. Eur J Radiol 2012; 81 (06) 1173-1178
    CrossrefPubMedGoogle Scholar
  • 26 Hong K, Khwaja A, Liapi E, Torbenson MS, Georgiades CS, Geschwind JF. New intra-arterial drug delivery system for the treatment of liver cancer: preclinical assessment in a rabbit model of liver cancer. Clin Cancer Res 2006; 12 (08) 2563-2567
    CrossrefPubMedGoogle Scholar
  • 27 Varela M, Real MI, Burrel M. et al. Chemoembolization of hepatocellular carcinoma with drug eluting beads: efficacy and doxorubicin pharmacokinetics. J Hepatol 2007; 46 (03) 474-481
    CrossrefPubMedGoogle Scholar
  • 28 Golfieri R, Giampalma E, Renzulli M. et al; PRECISION ITALIA STUDY GROUP. Randomised controlled trial of doxorubicin-eluting beads vs conventional chemoembolisation for hepatocellular carcinoma. Br J Cancer 2014; 111 (02) 255-264
    CrossrefPubMedGoogle Scholar
  • 29 Facciorusso A, Di Maso M, Muscatiello N. Drug-eluting beads versus conventional chemoembolization for the treatment of unresectable hepatocellular carcinoma: a meta-analysis. Dig Liver Dis 2016; 48 (06) 571-577
    CrossrefPubMedGoogle Scholar
  • 30 Marin JJG, Briz O, Herraez E. et al. Molecular bases of the poor response of liver cancer to chemotherapy. Clin Res Hepatol Gastroenterol 2018; 42 (03) 182-192
    CrossrefPubMedGoogle Scholar
  • 31 Kudo M, Matsui O, Izumi N. et al; Liver Cancer Study Group of Japan. Transarterial chemoembolization failure/refractoriness: JSH-LCSGJ criteria 2014 update. Oncology 2014; 87 (Suppl. 01) 22-31
    CrossrefPubMedGoogle Scholar
  • 32 Marin JJ, Romero MR, Briz O. Molecular bases of liver cancer refractoriness to pharmacological treatment. Curr Med Chem 2010; 17 (08) 709-740
    CrossrefPubMedGoogle Scholar
  • 33 Wang XC, Wang F, Quan QQ. Roles of XRCC1/XPD/ERCC1 polymorphisms in predicting prognosis of hepatocellular carcinoma in patients receiving transcatheter arterial chemoembolization. Genet Test Mol Biomarkers 2016; 20 (04) 176-184
    CrossrefPubMedGoogle Scholar
  • 34 Yang S, Wang XQ. XLF-mediated NHEJ activity in hepatocellular carcinoma therapy resistance. BMC Cancer 2017; 17 (01) 344
    CrossrefPubMedGoogle Scholar
  • 35 Xue M, Wu Y, Fan W. et al. Prognostic value of TP53 mutation for transcatheter arterial chemoembolization failure/refractoriness in HBV-related advanced hepatocellular carcinoma. Cancer Res Treat 2020; 52 (03) 925-937
    CrossrefPubMedGoogle Scholar
  • 36 Zhao J, Wozniak A, Adams A. et al. SIRT7 regulates hepatocellular carcinoma response to therapy by altering the p53-dependent cell death pathway. J Exp Clin Cancer Res 2019; 38 (01) 252
    CrossrefPubMedGoogle Scholar
  • 37 Kim JK, Noh JH, Jung KH. et al. Sirtuin7 oncogenic potential in human hepatocellular carcinoma and its regulation by the tumor suppressors MiR-125a-5p and MiR-125b. Hepatology 2013; 57 (03) 1055-1067
    CrossrefPubMedGoogle Scholar
  • 38 Wei X, Zhao L, Ren R. et al. MiR-125b loss activated HIF1α/pAKT loop, leading to transarterial chemoembolization resistance in hepatocellular carcinoma. Hepatology 2021; 73 (04) 1381-1398
    CrossrefPubMedGoogle Scholar
  • 39 Kajihara J, Tomimaru Y, Eguchi H. et al. The clinical impact of Transcatheter Arterial Chemoembolization (TACE)-induced c-met upregulation on TACE refractoriness in hepatocellular carcinoma. Dig Dis Sci 2016; 61 (06) 1572-1581
    CrossrefPubMedGoogle Scholar
  • 40 Li XP, Yang XY, Biskup E. et al. Co-expression of CXCL8 and HIF-1α is associated with metastasis and poor prognosis in hepatocellular carcinoma. Oncotarget 2015; 6 (26) 22880-22889
    CrossrefPubMedGoogle Scholar
  • 41 Martin SP, Fako V, Dang H. et al. PKM2 inhibition may reverse therapeutic resistance to transarterial chemoembolization in hepatocellular carcinoma. J Exp Clin Cancer Res 2020; 39 (01) 99
    CrossrefPubMedGoogle Scholar
  • 42 Zeng Z, Ren J, O'Neil M. et al. Impact of stem cell marker expression on recurrence of TACE-treated hepatocellular carcinoma post liver transplantation. BMC Cancer 2012; 12: 584
    CrossrefPubMedGoogle Scholar
  • 43 Pan QZ, Pan K, Weng DS. et al. Annexin A3 promotes tumorigenesis and resistance to chemotherapy in hepatocellular carcinoma. Mol Carcinog 2015; 54 (08) 598-607
    CrossrefPubMedGoogle Scholar
  • 44 Pan QZ, Pan K, Wang QJ. et al. Annexin A3 as a potential target for immunotherapy of liver cancer stem-like cells. Stem Cells 2015; 33 (02) 354-366
    CrossrefPubMedGoogle Scholar
  • 45 Tong M, Fung TM, Luk ST. et al. ANXA3/JNK signaling promotes self-renewal and tumor growth, and its blockade provides a therapeutic target for hepatocellular carcinoma. Stem Cell Reports 2015; 5 (01) 45-59
    CrossrefPubMedGoogle Scholar
  • 46 Shao P, Qu WK, Wang CY. et al. MicroRNA-205-5p regulates the chemotherapeutic resistance of hepatocellular carcinoma cells by targeting PTEN/JNK/ANXA3 pathway. Am J Transl Res 2017; 9 (09) 4300-4307
    PubMedGoogle Scholar
  • 47 Ma XL, Jiang M, Zhao Y. et al. Application of serum annexin A3 in diagnosis, outcome prediction and therapeutic response evaluation for patients with hepatocellular carcinoma. Ann Surg Oncol 2018; 25 (06) 1686-1694
    CrossrefPubMedGoogle Scholar
  • 48 Liang Y, Liang Q, Qiao L, Xiao F. MicroRNAs modulate drug resistance-related mechanisms in hepatocellular carcinoma. Front Oncol 2020; 10: 920
    CrossrefPubMedGoogle Scholar
  • 49 Ali HEA, Emam AA, Zeeneldin AA. et al. Circulating miR-26a, miR-106b, miR-107 and miR-133b stratify hepatocellular carcinoma patients according to their response to transarterial chemoembolization. Clin Biochem 2019; 65: 45-52
    CrossrefPubMedGoogle Scholar
  • 50 Yao H, Yang Z, Lou Y. et al. miR-186 inhibits liver cancer stem cells expansion via targeting PTPN11. Front Oncol 2021; 11: 632976
    CrossrefPubMedGoogle Scholar
  • 51 Li J, Zhong X, Wang X. et al. miR-93 regulates liver tumor initiating cells expansion and predicts chemotherapeutic response of patients. Arch Biochem Biophys 2021; 703: 108871
    CrossrefPubMedGoogle Scholar
  • 52 Qu S, Zhang X, Wu Y, Li H, Zhai J, Wu D. miR-361-3p regulates liver tumor-initiating cells expansion and chemo-resistance. J Cancer 2021; 12 (05) 1483-1492
    CrossrefPubMedGoogle Scholar
  • 53 Zhu AX, Rosmorduc O, Evans TR. et al. SEARCH: a phase III, randomized, double-blind, placebo-controlled trial of sorafenib plus erlotinib in patients with advanced hepatocellular carcinoma. J Clin Oncol 2015; 33 (06) 559-566
    CrossrefPubMedGoogle Scholar
  • 54 Koeberle D, Dufour JF, Demeter G. et al; Swiss Group for Clinical Cancer Research (SAKK). Sorafenib with or without everolimus in patients with advanced hepatocellular carcinoma (HCC): a randomized multicenter, multinational phase II trial (SAKK 77/08 and SASL 29). Ann Oncol 2016; 27 (05) 856-861
    CrossrefPubMedGoogle Scholar
  • 55 Nahm JH, Rhee H, Kim H. et al. Increased expression of stemness markers and altered tumor stroma in hepatocellular carcinoma under TACE-induced hypoxia: a biopsy and resection matched study. Oncotarget 2017; 8 (59) 99359-99371
    CrossrefPubMedGoogle Scholar
  • 56 Lencioni R, Llovet JM, Han G. et al. Sorafenib or placebo plus TACE with doxorubicin-eluting beads for intermediate stage HCC: the SPACE trial. J Hepatol 2016; 64 (05) 1090-1098
    CrossrefPubMedGoogle Scholar
  • 57 Meyer T, Fox R, Ma YT. et al. Sorafenib in combination with transarterial chemoembolisation in patients with unresectable hepatocellular carcinoma (TACE 2): a randomised placebo-controlled, double-blind, phase 3 trial. Lancet Gastroenterol Hepatol 2017; 2 (08) 565-575
    CrossrefPubMedGoogle Scholar
  • 58 Kudo M, Ueshima K, Ikeda M. et al; TACTICS study group. Randomised, multicentre prospective trial of transarterial chemoembolisation (TACE) plus sorafenib as compared with TACE alone in patients with hepatocellular carcinoma: TACTICS trial. Gut 2020; 69 (08) 1492-1501
    CrossrefPubMedGoogle Scholar
  • 59 Kudo M, Finn RS, Qin S. et al. Lenvatinib versus sorafenib in first-line treatment of patients with unresectable hepatocellular carcinoma: a randomised phase 3 non-inferiority trial. Lancet 2018; 391 (10126): 1163-1173
    CrossrefPubMedGoogle Scholar
  • 60 Bruix J, Qin S, Merle P. et al; RESORCE Investigators. Regorafenib for patients with hepatocellular carcinoma who progressed on sorafenib treatment (RESORCE): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet 2017; 389 (10064): 56-66
    CrossrefPubMedGoogle Scholar
  • 61 Finn RS, Merle P, Granito A. et al. Outcomes of sequential treatment with sorafenib followed by regorafenib for HCC: additional analyses from the phase III RESORCE trial. J Hepatol 2018; 69 (02) 353-358
    CrossrefPubMedGoogle Scholar
  • 62 Abou-Alfa GK, Meyer T, Cheng AL. et al. Cabozantinib in patients with advanced and progressing hepatocellular carcinoma. N Engl J Med 2018; 379 (01) 54-63
    CrossrefPubMedGoogle Scholar
  • 63 Zhu AX, Park JO, Ryoo BY. et al; REACH Trial Investigators. Ramucirumab versus placebo as second-line treatment in patients with advanced hepatocellular carcinoma following first-line therapy with sorafenib (REACH): a randomised, double-blind, multicentre, phase 3 trial. Lancet Oncol 2015; 16 (07) 859-870
    CrossrefPubMedGoogle Scholar
  • 64 Zhu AX, Kang YK, Yen CJ. et al; REACH-2 study investigators. Ramucirumab after sorafenib in patients with advanced hepatocellular carcinoma and increased α-fetoprotein concentrations (REACH-2): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol 2019; 20 (02) 282-296
    CrossrefPubMedGoogle Scholar
  • 65 Cheng AL, Kang YK, Lin DY. et al. Sunitinib versus sorafenib in advanced hepatocellular cancer: results of a randomized phase III trial. J Clin Oncol 2013; 31 (32) 4067-4075
    CrossrefPubMedGoogle Scholar
  • 66 Johnson PJ, Qin S, Park JW. et al. Brivanib versus sorafenib as first-line therapy in patients with unresectable, advanced hepatocellular carcinoma: results from the randomized phase III BRISK-FL study. J Clin Oncol 2013; 31 (28) 3517-3524
    CrossrefPubMedGoogle Scholar
  • 67 Cainap C, Qin S, Huang WT. et al. Linifanib versus sorafenib in patients with advanced hepatocellular carcinoma: results of a randomized phase III trial. J Clin Oncol 2015; 33 (02) 172-179
    CrossrefPubMedGoogle Scholar
  • 68 Cheng AL, Thongprasert S, Lim HY. et al. Randomized, open-label phase 2 study comparing frontline dovitinib versus sorafenib in patients with advanced hepatocellular carcinoma. Hepatology 2016; 64 (03) 774-784
    CrossrefPubMedGoogle Scholar
  • 69 Bi F, Qin S, Gu S. et al. Donafenib versus sorafenib as first-line therapy in advanced hepatocellular carcinoma: an open-label, randomized, multicenter phase ii/iii trial. J Clin Oncol 2020; 38 (suppl): Abstract 4506
    CrossrefPubMedGoogle Scholar
  • 70 Hou Z, Zhu K, Yang X. et al. Apatinib as first-line treatment in patients with advanced hepatocellular carcinoma: a phase II clinical trial. Ann Transl Med 2020; 8 (17) 1047
    CrossrefPubMedGoogle Scholar
  • 71 Hiraoka A, Kumada T, Hatanaka T. et al. Real-life Practice Experts for HCC (RELPEC) Study Group, HCC 48 Group (hepatocellular carcinoma experts from 48 clinics in Japan), and GLSG (Gunma Liver Study Group). Therapeutic efficacy of lenvatinib as third-line treatment after regorafenib for unresectable hepatocellular carcinoma progression. Hepatol Res 2021; 51 (08) 880-889
    CrossrefPubMedGoogle Scholar
  • 72 Kelley RK, Gane E, Assenat E. et al. A phase 2 study of galunisertib (TGF-β1 receptor type I inhibitor) and sorafenib in patients with advanced hepatocellular carcinoma. Clin Transl Gastroenterol 2019; 10 (07) e00056
    CrossrefPubMedGoogle Scholar
  • 73 Lim HY, Merle P, Weiss KH. et al. Phase II studies with refametinib or refametinib plus sorafenib in patients with RAS-mutated hepatocellular carcinoma. Clin Cancer Res 2018; 24 (19) 4650-4661
    CrossrefPubMedGoogle Scholar
  • 74 Marin JJ, Monte MJ, Blazquez AG, Macias RI, Serrano MA, Briz O. The role of reduced intracellular concentrations of active drugs in the lack of response to anticancer chemotherapy. Acta Pharmacol Sin 2014; 35 (01) 1-10
    CrossrefPubMedGoogle Scholar
  • 75 Simi AK, Pang MF, Nelson CM. Extracellular matrix stiffness exists in a feedback loop that drives tumor progression. Adv Exp Med Biol 2018; 1092: 57-67
    CrossrefPubMedGoogle Scholar
  • 76 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 (03) 1065-1073
    CrossrefPubMedGoogle Scholar
  • 77 Grimm D, Lieb J, Weyer V. et al. Organic Cation Transporter 1 (OCT1) mRNA expression in hepatocellular carcinoma as a biomarker for sorafenib treatment. BMC Cancer 2016; 16: 94
    CrossrefPubMedGoogle Scholar
  • 78 Al-Abdulla R, Lozano E, Macias RIR. et al. Epigenetic events involved in organic cation transporter 1-dependent impaired response of hepatocellular carcinoma to sorafenib. Br J Pharmacol 2019; 176 (06) 787-800
    CrossrefPubMedGoogle Scholar
  • 79 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 (09) 15846-15857
    CrossrefPubMedGoogle Scholar
  • 80 Garrison DA, Talebi Z, Eisenmann ED, Sparreboom A, Baker SD. Role of OATP1B1 and OATP1B3 in drug-drug interactions mediated by tyrosine kinase inhibitors. Pharmaceutics 2020; 12 (09) E856
    CrossrefPubMedGoogle Scholar
  • 81 Ohya H, Shibayama Y, Ogura J, Narumi K, Kobayashi M, Iseki K. Regorafenib is transported by the organic anion transporter 1B1 and the multidrug resistance protein 2. Biol Pharm Bull 2015; 38 (04) 582-586
    CrossrefPubMedGoogle Scholar
  • 82 Koide H, Tsujimoto M, Takeuchi A. et al. Substrate-dependent effects of molecular-targeted anticancer agents on activity of organic anion transporting polypeptide 1B1. Xenobiotica 2018; 48 (10) 1059-1071
    CrossrefPubMedGoogle Scholar
  • 83 Durmus S, van Hoppe S, Schinkel AH. The impact of Organic Anion-Transporting Polypeptides (OATPs) on disposition and toxicity of antitumor drugs: Insights from knockout and humanized mice. Drug Resist Updat 2016; 27: 72-88
    CrossrefPubMedGoogle Scholar
  • 84 Lacy S, Hsu B, Miles D, Aftab D, Wang R, Nguyen L. Metabolism and disposition of cabozantinib in healthy male volunteers and pharmacologic characterization of its major metabolites. Drug Metab Dispos 2015; 43 (08) 1190-1207
    CrossrefPubMedGoogle Scholar
  • 85 Wlcek K, Svoboda M, Riha J. et al. The analysis of organic anion transporting polypeptide (OATP) mRNA and protein patterns in primary and metastatic liver cancer. Cancer Biol Ther 2011; 11 (09) 801-811
    CrossrefPubMedGoogle Scholar
  • 86 Zhou T, Li S, Xiang D. et al. m6A RNA methylation-mediated HNF3γ reduction renders hepatocellular carcinoma dedifferentiation and sorafenib resistance. Signal Transduct Target Ther 2020; 5 (01) 296
    CrossrefPubMedGoogle Scholar
  • 87 Lee YS, Kim BH, Kim BC. et al. SLC15A2 genomic variation is associated with the extraordinary response of sorafenib treatment: whole-genome analysis in patients with hepatocellular carcinoma. Oncotarget 2015; 6 (18) 16449-16460
    CrossrefPubMedGoogle Scholar
  • 88 Hamblett KJ, Jacob AP, Gurgel JL. et al. SLC46A3 is required to transport catabolites of noncleavable antibody maytansine conjugates from the lysosome to the cytoplasm. Cancer Res 2015; 75 (24) 5329-5340
    CrossrefPubMedGoogle Scholar
  • 89 Kim JH, Matsubara T, Lee J. et al. Lysosomal SLC46A3 modulates hepatic cytosolic copper homeostasis. Nat Commun 2021; 12 (01) 290
    CrossrefPubMedGoogle Scholar
  • 90 Zhao Q, Zheng B, Meng S. et al. Increased expression of SLC46A3 to oppose the progression of hepatocellular carcinoma and its effect on sorafenib therapy. Biomed Pharmacother 2019; 114: 108864
    CrossrefPubMedGoogle Scholar
  • 91 Huang WC, Hsieh YL, Hung CM. et al. BCRP/ABCG2 inhibition sensitizes hepatocellular carcinoma cells to sorafenib. PLoS One 2013; 8 (12) e83627
    CrossrefPubMedGoogle Scholar
  • 92 Agarwal S, Sane R, Ohlfest JR, Elmquist WF. The role of the breast cancer resistance protein (ABCG2) in the distribution of sorafenib to the brain. J Pharmacol Exp Ther 2011; 336 (01) 223-233
    CrossrefPubMedGoogle Scholar
  • 93 Chen YL, Chen PM, Lin PY, Hsiau YT, Chu PY. ABCG2 overexpression confers poor outcomes in hepatocellular carcinoma of elderly patients. Anticancer Res 2016; 36 (06) 2983-2988
    PubMedGoogle Scholar
  • 94 Tandia M, Mhiri A, Paule B. et al. Correlation between clinical response to sorafenib in hepatocellular carcinoma treatment and polymorphisms of P-glycoprotein (ABCB1) and of breast cancer resistance protein (ABCG2): monocentric study. Cancer Chemother Pharmacol 2017; 79 (04) 759-766
    CrossrefPubMedGoogle Scholar
  • 95 Shibayama Y, Nakano K, Maeda H. et al. Multidrug resistance protein 2 implicates anticancer drug-resistance to sorafenib. Biol Pharm Bull 2011; 34 (03) 433-435
    CrossrefPubMedGoogle Scholar
  • 96 Ozeki T, Nagahama M, Fujita K. et al. Influence of CYP3A4/5 and ABC transporter polymorphisms on lenvatinib plasma trough concentrations in Japanese patients with thyroid cancer. Sci Rep 2019; 9 (01) 5404
    CrossrefPubMedGoogle Scholar
  • 97 Cabral LKD, Tiribelli C, Sukowati CHC. Sorafenib resistance in hepatocellular carcinoma: the relevance of genetic heterogeneity. Cancers (Basel) 2020; 12 (06) E1576
    CrossrefPubMedGoogle Scholar
  • 98 Miners JO, Chau N, Rowland A. et al. Inhibition of human UDP-glucuronosyltransferase enzymes by lapatinib, pazopanib, regorafenib and sorafenib: implications for hyperbilirubinemia. Biochem Pharmacol 2017; 129: 85-95
    CrossrefPubMedGoogle Scholar
  • 99 Guo XG, Wang ZH, Dong W, He XD, Liu FC, Liu H. Specific CYP450 genotypes in the Chinese population affect sorafenib toxicity in HBV/HCV-associated hepatocellular carcinoma patients. Biomed Environ Sci 2018; 31 (08) 586-595
    PubMedGoogle Scholar
  • 100 Ge Y, Chen S, Mu W. et al. Epigenetic regulation of UDP-Glucuronosyltransferase by microRNA-200a/-183: implications for responses to sorafenib treatment in patients with hepatocellular carcinoma. Cancer Lett 2019; 454: 14-25
    CrossrefPubMedGoogle Scholar
  • 101 Zheng YB, Zhan MX, Zhao W. et al. The relationship of kinase insert domain receptor gene polymorphisms and clinical outcome in advanced hepatocellular carcinoma patients treated with sorafenib. Med Oncol 2014; 31 (10) 209
    CrossrefPubMedGoogle Scholar
  • 102 Scartozzi M, Faloppi L, Svegliati Baroni G. et al. VEGF and VEGFR genotyping in the prediction of clinical outcome for HCC patients receiving sorafenib: the ALICE-1 study. Int J Cancer 2014; 135 (05) 1247-1256
    CrossrefPubMedGoogle Scholar
  • 103 Faloppi L, Puzzoni M, Casadei Gardini A. et al. Angiogenesis genotyping and clinical outcomes in patients with advanced hepatocellular carcinoma receiving sorafenib: the ALICE-2 study. Target Oncol 2020; 15 (01) 115-126
    CrossrefPubMedGoogle Scholar
  • 104 Negri FV, Dal Bello B, Porta C. et al. Expression of pERK and VEGFR-2 in advanced hepatocellular carcinoma and resistance to sorafenib treatment. Liver Int 2015; 35 (08) 2001-2008
    CrossrefPubMedGoogle Scholar
  • 105 Xiang Q, Chen W, Ren M. et al. Cabozantinib suppresses tumor growth and metastasis in hepatocellular carcinoma by a dual blockade of VEGFR2 and MET. Clin Cancer Res 2014; 20 (11) 2959-2970
    CrossrefPubMedGoogle Scholar
  • 106 Shigesawa T, Suda G, Kimura M. et al. Baseline angiopoietin-2 and FGF19 levels predict treatment response in patients receiving multikinase inhibitors for hepatocellular carcinoma. JGH Open 2020; 4 (05) 880-888
    CrossrefPubMedGoogle Scholar
  • 107 Finn RS, Kudo M, Cheng A-L. et al. 59PD - Final analysis of serum biomarkers in patients (pts) from the phase III study of lenvatinib (LEN) vs sorafenib (SOR) in unresectable hepatocellular carcinoma (uHCC) [REFLECT]. Ann Oncol 2018; 29 (Suppl. 08) VIII17-18
    CrossrefPubMedGoogle Scholar
  • 108 Cao L, Cheng H, Jiang Q, Li H, Wu Z. APEX1 is a novel diagnostic and prognostic biomarker for hepatocellular carcinoma. Aging (Albany NY) 2020; 12 (05) 4573-4591
    CrossrefPubMedGoogle Scholar
  • 109 Woo HG, Wang XW, Budhu A. et al. Association of TP53 mutations with stem cell-like gene expression and survival of patients with hepatocellular carcinoma. Gastroenterology 2011; 140 (03) 1063-1070
    CrossrefPubMedGoogle Scholar
  • 110 Schulze K, Nault JC, Villanueva A. Genetic profiling of hepatocellular carcinoma using next-generation sequencing. J Hepatol 2016; 65 (05) 1031-1042
    CrossrefPubMedGoogle Scholar
  • 111 Tang J, Sui CJ, Wang DF. et al. Targeted sequencing reveals the mutational landscape responsible for sorafenib therapy in advanced hepatocellular carcinoma. Theranostics 2020; 10 (12) 5384-5397
    CrossrefPubMedGoogle Scholar
  • 112 Weng X, Zeng L, Yan F, He M, Wu X, Zheng D. Cyclin-dependent kinase inhibitor 2B gene is associated with the sensitivity of hepatoma cells to Sorafenib. OncoTargets Ther 2019; 12: 5025-5036
    CrossrefPubMedGoogle Scholar
  • 113 Lin H, Zhang R, Wu W, Lei L. Comprehensive network analysis of the molecular mechanisms associated with sorafenib resistance in hepatocellular carcinoma. Cancer Genet 2020; 245: 27-34
    CrossrefPubMedGoogle Scholar
  • 114 Huang H, Wang X, Wang C, Zhuo L, Luo S, Han S. The miR-93 promotes proliferation by directly targeting PDCD4 in hepatocellular carcinoma. Neoplasma 2017; 64 (05) 770-777
    CrossrefPubMedGoogle Scholar
  • 115 Ohta K, Hoshino H, Wang J. et al. MicroRNA-93 activates c-Met/PI3K/Akt pathway activity in hepatocellular carcinoma by directly inhibiting PTEN and CDKN1A. Oncotarget 2015; 6 (05) 3211-3224
    CrossrefPubMedGoogle Scholar
  • 116 Gramantieri L, Fornari F, Ferracin M. et al. MicroRNA-221 targets Bmf in hepatocellular carcinoma and correlates with tumor multifocality. Clin Cancer Res 2009; 15 (16) 5073-5081
    CrossrefPubMedGoogle Scholar
  • 117 Fornari F, Pollutri D, Patrizi C. et al. In hepatocellular carcinoma miR-221 modulates sorafenib resistance through inhibition of caspase-3-mediated apoptosis. Clin Cancer Res 2017; 23 (14) 3953-3965
    CrossrefPubMedGoogle Scholar
  • 118 Perugorria MJ, Olaizola P, Labiano I. et al. Wnt-β-catenin signalling in liver development, health and disease. Nat Rev Gastroenterol Hepatol 2019; 16 (02) 121-136
    CrossrefPubMedGoogle Scholar
  • 119 Tutusaus A, Stefanovic M, Boix L. et al. Antiapoptotic BCL-2 proteins determine sorafenib/regorafenib resistance and BH3-mimetic efficacy in hepatocellular carcinoma. Oncotarget 2018; 9 (24) 16701-16717
    CrossrefPubMedGoogle Scholar
  • 120 Liu F, Dong X, Lv H. et al. Targeting hypoxia-inducible factor-2α enhances sorafenib antitumor activity via β-catenin/C-Myc-dependent pathways in hepatocellular carcinoma. Oncol Lett 2015; 10 (02) 778-784
    CrossrefPubMedGoogle Scholar
  • 121 Kim JB, Lee M, Park SY. et al. Sorafenib inhibits cancer side population cells by targeting c‑Jun N‑terminal kinase signaling. Mol Med Rep 2015; 12 (06) 8247-8252
    CrossrefPubMedGoogle Scholar
  • 122 Teufel M, Seidel H, Köchert K. et al. Biomarkers associated with response to regorafenib in patients with hepatocellular carcinoma. Gastroenterology 2019; 156 (06) 1731-1741
    CrossrefPubMedGoogle Scholar
  • 123 Chen KF, Chen HL, Tai WT. et al. Activation of phosphatidylinositol 3-kinase/Akt signaling pathway mediates acquired resistance to sorafenib in hepatocellular carcinoma cells. J Pharmacol Exp Ther 2011; 337 (01) 155-161
    CrossrefPubMedGoogle Scholar
  • 124 Caruso S, Calatayud AL, Pilet J. et al. Analysis of liver cancer cell lines identifies agents with likely efficacy against hepatocellular carcinoma and markers of response. Gastroenterology 2019; 157 (03) 760-776
    CrossrefPubMedGoogle Scholar
  • 125 Chen KF, Tai WT, Liu TH. et al. Sorafenib overcomes TRAIL resistance of hepatocellular carcinoma cells through the inhibition of STAT3. Clin Cancer Res 2010; 16 (21) 5189-5199
    CrossrefPubMedGoogle Scholar
  • 126 Ding X, He M, Chan AWH. et al. Genomic and epigenomic features of primary and recurrent hepatocellular carcinomas. Gastroenterology 2019; 157 (06) 1630-1645.e6
    CrossrefPubMedGoogle Scholar
  • 127 Dimri M, Satyanarayana A. Molecular signaling pathways and therapeutic targets in hepatocellular carcinoma. Cancers (Basel) 2020; 12 (02) E491
    CrossrefPubMedGoogle Scholar
  • 128 Liu K, Liu S, Zhang W. et al. miR-494 promotes cell proliferation, migration and invasion, and increased sorafenib resistance in hepatocellular carcinoma by targeting PTEN. Oncol Rep 2015; 34 (02) 1003-1010
    CrossrefPubMedGoogle Scholar
  • 129 He C, Dong X, Zhai B. et al. MiR-21 mediates sorafenib resistance of hepatocellular carcinoma cells by inhibiting autophagy via the PTEN/Akt pathway. Oncotarget 2015; 6 (30) 28867-28881
    CrossrefPubMedGoogle Scholar
  • 130 Wen DY, Huang JC, Wang JY. et al. Potential clinical value and putative biological function of miR-122-5p in hepatocellular carcinoma: a comprehensive study using microarray and RNA sequencing data. Oncol Lett 2018; 16 (06) 6918-6929
    PubMedGoogle Scholar
  • 131 Xu Y, Huang J, Ma L. et al. MicroRNA-122 confers sorafenib resistance to hepatocellular carcinoma cells by targeting IGF-1R to regulate RAS/RAF/ERK signaling pathways. Cancer Lett 2016; 371 (02) 171-181
    CrossrefPubMedGoogle Scholar
  • 132 Liang Y, Zheng T, Song R. et al. Hypoxia-mediated sorafenib resistance can be overcome by EF24 through Von Hippel-Lindau tumor suppressor-dependent HIF-1α inhibition in hepatocellular carcinoma. Hepatology 2013; 57 (05) 1847-1857
    CrossrefPubMedGoogle Scholar
  • 133 Jiang Y, Chen P, Hu K. et al. Inflammatory microenvironment of fibrotic liver promotes hepatocellular carcinoma growth, metastasis and sorafenib resistance through STAT3 activation. J Cell Mol Med 2021; 25 (03) 1568-1582
    CrossrefPubMedGoogle Scholar
  • 134 Tan W, Luo X, Li W. et al. TNF-α is a potential therapeutic target to overcome sorafenib resistance in hepatocellular carcinoma. EBioMedicine 2019; 40: 446-456
    CrossrefPubMedGoogle Scholar
  • 135 Wang D, Yang EB, Cheng LY. Modulation of EGF receptor by tumor necrosis factor-alpha in human hepatocellular carcinoma HepG2 cells. Anticancer Res 1996; 16 (5A): 3001-3006
    PubMedGoogle Scholar
  • 136 Zhou SL, Zhou ZJ, Hu ZQ. et al. Tumor-associated neutrophils recruit macrophages and T-regulatory cells to promote progression of hepatocellular carcinoma and resistance to sorafenib. Gastroenterology 2016; 150 (07) 1646-1658.e17
    CrossrefPubMedGoogle Scholar
  • 137 Giannelli G, Koudelkova P, Dituri F, Mikulits W. Role of epithelial to mesenchymal transition in hepatocellular carcinoma. J Hepatol 2016; 65 (04) 798-808
    CrossrefPubMedGoogle Scholar
  • 138 Kim BH, Park JW, Kim JS, Lee SK, Hong EK. Stem cell markers predict the response to sorafenib in patients with hepatocellular carcinoma. Gut Liver 2019; 13 (03) 342-348
    CrossrefPubMedGoogle Scholar
  • 139 Ma S, Lee TK, Zheng BJ, Chan KW, Guan XY. CD133+ HCC cancer stem cells confer chemoresistance by preferential expression of the Akt/PKB survival pathway. Oncogene 2008; 27 (12) 1749-1758
    CrossrefPubMedGoogle Scholar
  • 140 Chen WC, Chang YS, Hsu HP. et al. Therapeutics targeting CD90-integrin-AMPK-CD133 signal axis in liver cancer. Oncotarget 2015; 6 (40) 42923-42937
    CrossrefPubMedGoogle Scholar
  • 141 Jia Q, Zhang X, Deng T, Gao J. Positive correlation of Oct4 and ABCG2 to chemotherapeutic resistance in CD90(+)CD133(+) liver cancer stem cells. Cell Reprogram 2013; 15 (02) 143-150
    CrossrefPubMedGoogle Scholar
  • 142 Wang M, Wang Z, Zhi X. et al. SOX9 enhances sorafenib resistance through upregulating ABCG2 expression in hepatocellular carcinoma. Biomed Pharmacother 2020; 129: 110315
    CrossrefPubMedGoogle Scholar
  • 143 Lu S, Yao Y, Xu G. et al. CD24 regulates sorafenib resistance via activating autophagy in hepatocellular carcinoma. Cell Death Dis 2018; 9 (06) 646
    CrossrefPubMedGoogle Scholar
  • 144 Ko CJ, Li CJ, Wu MY, Chu PY. Overexpression of epithelial cell adhesion molecule as a predictor of poor outcome in patients with hepatocellular carcinoma. Exp Ther Med 2018; 16 (06) 4810-4816
    PubMedGoogle Scholar
  • 145 Tong M, Che N, Zhou L. et al. Efficacy of annexin A3 blockade in sensitizing hepatocellular carcinoma to sorafenib and regorafenib. J Hepatol 2018; 69 (04) 826-839
    CrossrefPubMedGoogle Scholar
  • 146 Gurzu S, Kobori L, Fodor D, Jung I. Epithelial mesenchymal and endothelial mesenchymal transitions in hepatocellular carcinoma: a review. BioMed Res Int 2019; 2019: 2962580
    CrossrefPubMedGoogle Scholar
  • 147 Liu YC, Yeh CT, Lin KH. Cancer stem cell functions in hepatocellular carcinoma and comprehensive therapeutic strategies. Cells 2020; 9 (06) E1331
    CrossrefPubMedGoogle Scholar
  • 148 Vilchez V, Turcios L, Marti F, Gedaly R. Targeting Wnt/β-catenin pathway in hepatocellular carcinoma treatment. World J Gastroenterol 2016; 22 (02) 823-832
    CrossrefPubMedGoogle Scholar
  • 149 Yamashita T, Budhu A, Forgues M, Wang XW. Activation of hepatic stem cell marker EpCAM by Wnt-beta-catenin signaling in hepatocellular carcinoma. Cancer Res 2007; 67 (22) 10831-10839
    CrossrefPubMedGoogle Scholar
  • 150 Fan Z, Duan J, Wang L. et al. PTK2 promotes cancer stem cell traits in hepatocellular carcinoma by activating Wnt/β-catenin signaling. Cancer Lett 2019; 450: 132-143
    CrossrefPubMedGoogle Scholar
  • 151 Lin TH, Shao YY, Chan SY, Huang CY, Hsu CH, Cheng AL. High serum transforming growth factor-β1 levels predict outcome in hepatocellular carcinoma patients treated with sorafenib. Clin Cancer Res 2015; 21 (16) 3678-3684
    CrossrefPubMedGoogle Scholar
  • 152 Xia H, Ooi LL, Hui KM. MicroRNA-216a/217-induced epithelial-mesenchymal transition targets PTEN and SMAD7 to promote drug resistance and recurrence of liver cancer. Hepatology 2013; 58 (02) 629-641
    CrossrefPubMedGoogle Scholar
  • 153 Li B, Liu D, Yang P, Li HY, Wang D. miR-613 inhibits liver cancer stem cell expansion by regulating SOX9 pathway. Gene 2019; 707: 78-85
    CrossrefPubMedGoogle Scholar
  • 154 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 (01) 4
    CrossrefPubMedGoogle Scholar
  • 155 Kruger S, Ilmer M, Kobold S. et al. Advances in cancer immunotherapy 2019—latest trends. J Exp Clin Cancer Res 2019; 38 (01) 268
    CrossrefPubMedGoogle Scholar
  • 156 Kole C, Charalampakis N, Tsakatikas S. et al. Immunotherapy for hepatocellular carcinoma: a 2021 update. Cancers (Basel) 2020; 12 (10) E2859
    CrossrefPubMedGoogle Scholar
  • 157 El-Khoueiry AB, Sangro B, Yau T. et al. Nivolumab in patients with advanced hepatocellular carcinoma (CheckMate 040): an open-label, non-comparative, phase 1/2 dose escalation and expansion trial. Lancet 2017; 389 (10088): 2492-2502
    CrossrefPubMedGoogle Scholar
  • 158 Zhu AX, Finn RS, Edeline J. et al; KEYNOTE-224 investigators. Pembrolizumab in patients with advanced hepatocellular carcinoma previously treated with sorafenib (KEYNOTE-224): a non-randomised, open-label phase 2 trial. Lancet Oncol 2018; 19 (07) 940-952
    CrossrefPubMedGoogle Scholar
  • 159 Yau T, Kang YK, Kim TY. et al. Efficacy and safety of nivolumab plus ipilimumab in patients with advanced hepatocellular carcinoma previously treated with sorafenib: the CheckMate 040 randomized clinical trial. JAMA Oncol 2020; 6 (11) e204564
    CrossrefPubMedGoogle Scholar
  • 160 Finn RS, Qin S, Ikeda M. et al; IMbrave150 Investigators. Atezolizumab plus bevacizumab in unresectable hepatocellular carcinoma. N Engl J Med 2020; 382 (20) 1894-1905
    CrossrefPubMedGoogle Scholar
  • 161 Rabinovich GA, Gabrilovich D, Sotomayor EM. Immunosuppressive strategies that are mediated by tumor cells. Annu Rev Immunol 2007; 25: 267-296
    CrossrefPubMedGoogle Scholar
  • 162 Shalapour S, Karin M. Pas de Deux: control of anti-tumor immunity by cancer-associated inflammation. Immunity 2019; 51 (01) 15-26
    CrossrefPubMedGoogle Scholar
  • 163 Sangro B, Melero I, Wadhawan S. et al. Association of inflammatory biomarkers with clinical outcomes in nivolumab-treated patients with advanced hepatocellular carcinoma. J Hepatol 2020; 73 (06) 1460-1469
    CrossrefPubMedGoogle Scholar
  • 164 Lim CJ, Lee YH, Pan L. et al. Multidimensional analyses reveal distinct immune microenvironment in hepatitis B virus-related hepatocellular carcinoma. Gut 2019; 68 (05) 916-927
    CrossrefPubMedGoogle Scholar
  • 165 Sia D, Jiao Y, Martinez-Quetglas I. et al. Identification of an immune-specific class of hepatocellular carcinoma, based on molecular features. Gastroenterology 2017; 153 (03) 812-826
    CrossrefPubMedGoogle Scholar
  • 166 Liu CQ, Xu J, Zhou ZG. et al. Expression patterns of programmed death ligand 1 correlate with different microenvironments and patient prognosis in hepatocellular carcinoma. Br J Cancer 2018; 119 (01) 80-88
    CrossrefPubMedGoogle Scholar
  • 167 Calderaro J, Rousseau B, Amaddeo G. et al. Programmed death ligand 1 expression in hepatocellular carcinoma: relationship with clinical and pathological features. Hepatology 2016; 64 (06) 2038-2046
    CrossrefPubMedGoogle Scholar
  • 168 Pfister D, Núñez NG, Pinyol R. et al. NASH limits anti-tumour surveillance in immunotherapy-treated HCC. Nature 2021; 592 (7854): 450-456
    CrossrefPubMedGoogle Scholar
  • 169 Schulte LA, López-Gil JC, Sainz Jr B, Hermann PC. The cancer stem cell in hepatocellular carcinoma. Cancers (Basel) 2020; 12 (03) E684
    CrossrefPubMedGoogle Scholar
  • 170 Ruiu R, Tarone L, Rolih V. et al. Cancer stem cell immunology and immunotherapy: harnessing the immune system against cancer's source. Prog Mol Biol Transl Sci 2019; 164: 119-188
    CrossrefPubMedGoogle Scholar
  • 171 Chan LH, Luk ST, Ma S. Turning hepatic cancer stem cells inside out–a deeper understanding through multiple perspectives. Mol Cells 2015; 38 (03) 202-209
    CrossrefPubMedGoogle Scholar
  • 172 Willingham SB, Volkmer JP, Gentles AJ. et al. The CD47-signal regulatory protein alpha (SIRPa) interaction is a therapeutic target for human solid tumors. Proc Natl Acad Sci U S A 2012; 109 (17) 6662-6667
    CrossrefPubMedGoogle Scholar
  • 173 Ni H, Cao L, Wu Z. et al. Combined strategies for effective cancer immunotherapy with a novel anti-CD47 monoclonal antibody. Cancer Immunol Immunother 2021; (e-pub ahead of print) DOI: 10.1007/s00262-021-02989-2.
    CrossrefPubMedGoogle Scholar
  • 174 Ruiz de Galarreta M, Bresnahan E, Molina-Sánchez P. et al. β-Catenin activation promotes immune escape and resistance to anti-PD-1 therapy in hepatocellular carcinoma. Cancer Discov 2019; 9 (08) 1124-1141
    CrossrefPubMedGoogle Scholar
  • 175 Harding JJ, Nandakumar S, Armenia J. et al. Prospective genotyping of hepatocellular carcinoma: clinical implications of next-generation sequencing for matching patients to targeted and immune therapies. Clin Cancer Res 2019; 25 (07) 2116-2126
    CrossrefPubMedGoogle Scholar
  • 176 Milosa F, Critelli RM, Lasagni S. et al. Prognostic significance of hypoxic and metabolic gene profiling in hepatocellular carcinoma. Liver Cancer International 2021; 2 (01) 15-26
    CrossrefPubMedGoogle Scholar
  • 177 Brown ZJ, Yu SJ, Heinrich B. et al. Indoleamine 2,3-dioxygenase provides adaptive resistance to immune checkpoint inhibitors in hepatocellular carcinoma. Cancer Immunol Immunother 2018; 67 (08) 1305-1315
    CrossrefPubMedGoogle Scholar
  • 178 Casak SJ, Donoghue M, Fashoyin-Aje L. et al. FDA approval summary: atezolizumab plus bevacizumab for the treatment of patients with advanced unresectable or metastatic hepatocellular carcinoma. Clin Cancer Res 2021; 27 (07) 1836-1841
    CrossrefPubMedGoogle Scholar
  • 179 Rieth J, Subramanian S. Mechanisms of intrinsic tumor resistance to immunotherapy. Int J Mol Sci 2018; 19 (05) E1340
    CrossrefPubMedGoogle Scholar
  • 180 Yarchoan M, Xing D, Luan L. et al. Characterization of the immune microenvironment in hepatocellular carcinoma. Clin Cancer Res 2017; 23 (23) 7333-7339
    CrossrefPubMedGoogle Scholar
  • 181 He X, Xu C. Immune checkpoint signaling and cancer immunotherapy. Cell Res 2020; 30 (08) 660-669
    CrossrefPubMedGoogle Scholar