Semin Liver Dis
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.

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.



Publication History

Publication Date:
20 September 2021 (online)

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