Molecular Bases of Drug Resistance in Hepatocellular Carcinoma

doi:10.3390/cancers12061663

Review

. 2020 Jun 23;12(6):1663.

doi: 10.3390/cancers12061663.

Molecular Bases of Drug Resistance in Hepatocellular Carcinoma

Jose J G Marin^{1

2}, Rocio I R Macias^{1

2}, Maria J Monte^{1

2}, Marta R Romero^{1

2}, Maitane Asensio¹, Anabel Sanchez-Martin¹, Candela Cives-Losada¹, Alvaro G Temprano¹, Ricardo Espinosa-Escudero¹, Maria Reviejo¹, Laura H Bohorquez¹, Oscar Briz^{1

2}

Affiliations

¹ Experimental Hepatology and Drug Targeting (HEVEFARM) Group, University of Salamanca, IBSAL, 37007 Salamanca, Spain.
² Center for the Study of Liver and Gastrointestinal Diseases (CIBERehd), Carlos III National Institute of Health, 28029 Madrid, Spain.

PMID: 32585893
PMCID: PMC7352164
DOI: 10.3390/cancers12061663

Review

Molecular Bases of Drug Resistance in Hepatocellular Carcinoma

Jose J G Marin et al. Cancers (Basel). 2020.

. 2020 Jun 23;12(6):1663.

doi: 10.3390/cancers12061663.

Authors

Affiliations

¹ Experimental Hepatology and Drug Targeting (HEVEFARM) Group, University of Salamanca, IBSAL, 37007 Salamanca, Spain.
² Center for the Study of Liver and Gastrointestinal Diseases (CIBERehd), Carlos III National Institute of Health, 28029 Madrid, Spain.

PMID: 32585893
PMCID: PMC7352164
DOI: 10.3390/cancers12061663

Abstract

The poor outcome of patients with non-surgically removable advanced hepatocellular carcinoma (HCC), the most frequent type of primary liver cancer, is mainly due to the high refractoriness of this aggressive tumor to classical chemotherapy. Novel pharmacological approaches based on the use of inhibitors of tyrosine kinases (TKIs), mainly sorafenib and regorafenib, have provided only a modest prolongation of the overall survival in these HCC patients. The present review is an update of the available information regarding our understanding of the molecular bases of mechanisms of chemoresistance (MOC) with a significant impact on the response of HCC to existing pharmacological tools, which include classical chemotherapeutic agents, TKIs and novel immune-sensitizing strategies. Many of the more than one hundred genes involved in seven MOC have been identified as potential biomarkers to predict the failure of treatment, as well as druggable targets to develop novel strategies aimed at increasing the sensitivity of HCC to pharmacological treatments.

Keywords: DNA repair; apoptosis; cancer stem cell; epithelial-mesenchymal transition; liver cancer; metabolism; multidrug resistance; refractoriness; transport; tumor environment.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

**Figure 1**
Proteins and non-coding RNAs accounting for chemoresistance in hepatocellular carcinoma. ICI, immune checkpoint inhibitors; MOC, mechanism of chemoresistance.

See this image and copyright information in PMC

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References

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[1] Ferlay J., Colombet M., Soerjomataram I., Mathers C., Parkin D.M., Pineros M., Znaor A., Bray F. Estimating the global cancer incidence and mortality in 2018: GLOBOCAN sources and methods. Int. J. Cancer. 2019;144:1941–1953. doi: 10.1002/ijc.31937. - DOI - PubMed

[2] Ferlay J., Colombet M., Soerjomataram I., Mathers C., Parkin D.M., Pineros M., Znaor A., Bray F. Estimating the global cancer incidence and mortality in 2018: GLOBOCAN sources and methods. Int. J. Cancer. 2019;144:1941–1953. doi: 10.1002/ijc.31937. - DOI - PubMed

[3] Marin J.J.G., Briz O., Herraez E., Lozano E., Asensio M., Di Giacomo S., Romero M.R., Osorio-Padilla L.M., Santos-Llamas A.I., Serrano M.A., et al. Molecular bases of the poor response of liver cancer to chemotherapy. Clin. Res. Hepatol. Gastroenterol. 2018;42:182–192. doi: 10.1016/j.clinre.2017.12.006. - DOI - PubMed

[4] Marin J.J.G., Briz O., Herraez E., Lozano E., Asensio M., Di Giacomo S., Romero M.R., Osorio-Padilla L.M., Santos-Llamas A.I., Serrano M.A., et al. Molecular bases of the poor response of liver cancer to chemotherapy. Clin. Res. Hepatol. Gastroenterol. 2018;42:182–192. doi: 10.1016/j.clinre.2017.12.006. - DOI - PubMed

[5] Cervello M., Emma M.R., Augello G., Cusimano A., Giannitrapani L., Soresi M., Akula S.M., Abrams S.L., Steelman L.S., Gulino A., et al. New landscapes and horizons in hepatocellular carcinoma therapy. Aging (Albany NY) 2020;12:3053–3094. doi: 10.18632/aging.102777. - DOI - PMC - PubMed

[6] Cervello M., Emma M.R., Augello G., Cusimano A., Giannitrapani L., Soresi M., Akula S.M., Abrams S.L., Steelman L.S., Gulino A., et al. New landscapes and horizons in hepatocellular carcinoma therapy. Aging (Albany NY) 2020;12:3053–3094. doi: 10.18632/aging.102777. - DOI - PMC - PubMed

[7] Wilhelm S.M., Adnane L., Newell P., Villanueva A., Llovet J.M., Lynch M. Preclinical overview of sorafenib, a multikinase inhibitor that targets both Raf and VEGF and PDGF receptor tyrosine kinase signaling. Mol. Cancer Ther. 2008;7:3129–3140. doi: 10.1158/1535-7163.MCT-08-0013. - DOI - PubMed

[8] Wilhelm S.M., Adnane L., Newell P., Villanueva A., Llovet J.M., Lynch M. Preclinical overview of sorafenib, a multikinase inhibitor that targets both Raf and VEGF and PDGF receptor tyrosine kinase signaling. Mol. Cancer Ther. 2008;7:3129–3140. doi: 10.1158/1535-7163.MCT-08-0013. - DOI - PubMed

[9] Vogel A., Saborowski A. Current strategies for the treatment of intermediate and advanced hepatocellular carcinoma. Cancer Treat Rev. 2020;82:101946. doi: 10.1016/j.ctrv.2019.101946. - DOI - PubMed

[10] Vogel A., Saborowski A. Current strategies for the treatment of intermediate and advanced hepatocellular carcinoma. Cancer Treat Rev. 2020;82:101946. doi: 10.1016/j.ctrv.2019.101946. - DOI - PubMed

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Molecular Bases of Drug Resistance in Hepatocellular Carcinoma

Affiliations

Molecular Bases of Drug Resistance in Hepatocellular Carcinoma

Authors

Affiliations

Abstract

Conflict of interest statement

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References

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