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Sorafenib Resistance in Hepatocellular Carcinoma: The Relevance of Genetic Heterogeneity

Despite advances in biomedicine, the incidence and the mortality of hepatocellular carcinoma (HCC) remain high. The majority of HCC cases are diagnosed in later stages leading to the less than optimal outcome of the treatments. Molecular targeted therapy with sorafenib, a dual-target inhibitor targe...

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Autores principales: Cabral, Loraine Kay D., Tiribelli, Claudio, Sukowati, Caecilia H. C.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7352671/
https://www.ncbi.nlm.nih.gov/pubmed/32549224
http://dx.doi.org/10.3390/cancers12061576
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author Cabral, Loraine Kay D.
Tiribelli, Claudio
Sukowati, Caecilia H. C.
author_facet Cabral, Loraine Kay D.
Tiribelli, Claudio
Sukowati, Caecilia H. C.
author_sort Cabral, Loraine Kay D.
collection PubMed
description Despite advances in biomedicine, the incidence and the mortality of hepatocellular carcinoma (HCC) remain high. The majority of HCC cases are diagnosed in later stages leading to the less than optimal outcome of the treatments. Molecular targeted therapy with sorafenib, a dual-target inhibitor targeting the serine-threonine kinase Raf and the tyrosine kinases VEGFR/PDGFR, is at present the main treatment for advanced-stage HCC, either in a single or combinatory regimen. However, it was observed in a large number of patients that its effectiveness is hampered by drug resistance. HCC is highly heterogeneous, within the tumor and among individuals, and this influences disease progression, classification, prognosis, and naturally cellular susceptibility to drug resistance. This review aims to provide an insight on how HCC heterogeneity influences the different primary mechanisms of chemoresistance against sorafenib including reduced drug intake, enhanced drug efflux, intracellular drug metabolism, alteration of molecular targets, activation/inactivation of signaling pathways, changes in the DNA repair machinery, and negative balance between apoptosis and survival of the cancer cells. The diverse variants, mutations, and polymorphisms in molecules and their association with drug response can be a helpful tool in treatment decision making. Accordingly, the existence of heterogeneous biomarkers in the tumor must be considered to strengthen multi-target strategies in patient-tailored treatment.
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spelling pubmed-73526712020-07-21 Sorafenib Resistance in Hepatocellular Carcinoma: The Relevance of Genetic Heterogeneity Cabral, Loraine Kay D. Tiribelli, Claudio Sukowati, Caecilia H. C. Cancers (Basel) Review Despite advances in biomedicine, the incidence and the mortality of hepatocellular carcinoma (HCC) remain high. The majority of HCC cases are diagnosed in later stages leading to the less than optimal outcome of the treatments. Molecular targeted therapy with sorafenib, a dual-target inhibitor targeting the serine-threonine kinase Raf and the tyrosine kinases VEGFR/PDGFR, is at present the main treatment for advanced-stage HCC, either in a single or combinatory regimen. However, it was observed in a large number of patients that its effectiveness is hampered by drug resistance. HCC is highly heterogeneous, within the tumor and among individuals, and this influences disease progression, classification, prognosis, and naturally cellular susceptibility to drug resistance. This review aims to provide an insight on how HCC heterogeneity influences the different primary mechanisms of chemoresistance against sorafenib including reduced drug intake, enhanced drug efflux, intracellular drug metabolism, alteration of molecular targets, activation/inactivation of signaling pathways, changes in the DNA repair machinery, and negative balance between apoptosis and survival of the cancer cells. The diverse variants, mutations, and polymorphisms in molecules and their association with drug response can be a helpful tool in treatment decision making. Accordingly, the existence of heterogeneous biomarkers in the tumor must be considered to strengthen multi-target strategies in patient-tailored treatment. MDPI 2020-06-15 /pmc/articles/PMC7352671/ /pubmed/32549224 http://dx.doi.org/10.3390/cancers12061576 Text en © 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Review
Cabral, Loraine Kay D.
Tiribelli, Claudio
Sukowati, Caecilia H. C.
Sorafenib Resistance in Hepatocellular Carcinoma: The Relevance of Genetic Heterogeneity
title Sorafenib Resistance in Hepatocellular Carcinoma: The Relevance of Genetic Heterogeneity
title_full Sorafenib Resistance in Hepatocellular Carcinoma: The Relevance of Genetic Heterogeneity
title_fullStr Sorafenib Resistance in Hepatocellular Carcinoma: The Relevance of Genetic Heterogeneity
title_full_unstemmed Sorafenib Resistance in Hepatocellular Carcinoma: The Relevance of Genetic Heterogeneity
title_short Sorafenib Resistance in Hepatocellular Carcinoma: The Relevance of Genetic Heterogeneity
title_sort sorafenib resistance in hepatocellular carcinoma: the relevance of genetic heterogeneity
topic Review
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7352671/
https://www.ncbi.nlm.nih.gov/pubmed/32549224
http://dx.doi.org/10.3390/cancers12061576
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