Antiapoptotic BCL-2 proteins determine Sorafenib/regorafenib resistance and BH3-mimetic efficacy in hepatocellular carcinoma

Sorafenib, systemic treatment for advanced hepatocellular carcinoma (HCC), and regorafenib, novel second line treatment after sorafenib failure, have efficacy limited by evasive mechanisms of acquired-drug resistance. BCL-2 proteins participate in the response to tyrosine kinase inhibitors; however,...

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Autores: Tutusaus, Anna, Stefanovic, Milica, Boix i Ferrero, Loreto, Cucarull, Blanca, Zamora, Aynara, Blasco, Laura, García de Frutos, Pablo, Reig, María, Fernández-Checa Torres, José Carlos, Marí García, Montserrat, Colell Riera, Anna, Bruix Tudó, Jordi, Morales Muñoz, Albert
Formato: artículo
Estado:Versión publicada
Fecha de publicación:2018
País:España
Recursos:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)
Repositorio:Recercat. Dipósit de la Recerca de Catalunya
OAI Identifier:oai:recercat.cat:2445/157937
Acesso em linha:https://hdl.handle.net/2445/157937
Access Level:acceso abierto
Palavra-chave:Càncer de fetge
Inhibidors enzimàtics
Tractament adjuvant del càncer
Liver cancer
Enzyme inhibitors
Adjuvant treatment of cancer
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spelling Antiapoptotic BCL-2 proteins determine Sorafenib/regorafenib resistance and BH3-mimetic efficacy in hepatocellular carcinomaTutusaus, AnnaStefanovic, MilicaBoix i Ferrero, LoretoCucarull, BlancaZamora, AynaraBlasco, LauraGarcía de Frutos, PabloReig, MaríaFernández-Checa Torres, José CarlosMarí García, MontserratColell Riera, AnnaBruix Tudó, JordiMorales Muñoz, AlbertCàncer de fetgeInhibidors enzimàticsTractament adjuvant del càncerLiver cancerEnzyme inhibitorsAdjuvant treatment of cancerSorafenib, systemic treatment for advanced hepatocellular carcinoma (HCC), and regorafenib, novel second line treatment after sorafenib failure, have efficacy limited by evasive mechanisms of acquired-drug resistance. BCL-2 proteins participate in the response to tyrosine kinase inhibitors; however, their role in HCC therapy with sorafenib/regorafenib remains uncertain. BH3-mimetic ABT-263 (navitoclax) enhanced sorafenib activity, inducing cell death via a mitochondrial caspase-dependent mechanism, after BCL-xL/BCL-2 inhibition. Sorafenib-resistant hepatoma cells (HepG2R and Hep3BR) exhibited altered mRNA expression of BCL-2 and other anti-apoptotic family members, such as MCL-1, priming drug-resistant cancer cells to death by BH3-mimetics. ABT-263 restored sorafenib efficacy in sorafenib-resistant cell lines and HCC mouse models. Moreover, in mice xenografts from patient-derived BCLC9 cells, better tumor response to sorafenib was associated to higher changes in the BCL-2 mRNA pattern. HCC non-treated patients displayed altered BCL-2, MCL-1 and BCL-xL mRNA levels respect to adjacent non-tumoral biopsies and an increased BCL-2/MCL-1 ratio, predictive of navitoclax efficacy. Moreover, regorafenib administration also modified the BCL-2/MCL-1 ratio and navitoclax sensitized hepatoma cells to regorafenib by a mitochondrial caspase-dependent mechanism. In conclusion, sorafenib/regorafenib response is determined by BCL-2 proteins, while increased BCL-2/MCL-1 ratio in HCC sensitizes drug resistant-tumors against ABT-263 co-administration. Thus, changes in the BCL-2 profile, altered in HCC patients, could help to follow-up sorafenib efficacy, allowing patient selection for combined therapy with BH3-mimetics or early switch them to second line therapy.Impact Journals2020202020182020info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersion17 p.application/pdfhttps://hdl.handle.net/2445/157937Articles publicats en revistes (Medicina)reponame:Recercat. Dipósit de la Recerca de Catalunyainstname:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)InglésReproducció del document publicat a: https://doi.org/10.18632/oncotarget.24673Oncotarget, 2018, vol. 9, num. 24, p. 16701-16717https://doi.org/10.18632/oncotarget.24673cc-by (c) Tutusaus, Anna et al., 2018http://creativecommons.org/licenses/by/3.0/esinfo:eu-repo/semantics/openAccessoai:recercat.cat:2445/1579372026-05-29T05:05:01Z
dc.title.none.fl_str_mv Antiapoptotic BCL-2 proteins determine Sorafenib/regorafenib resistance and BH3-mimetic efficacy in hepatocellular carcinoma
title Antiapoptotic BCL-2 proteins determine Sorafenib/regorafenib resistance and BH3-mimetic efficacy in hepatocellular carcinoma
spellingShingle Antiapoptotic BCL-2 proteins determine Sorafenib/regorafenib resistance and BH3-mimetic efficacy in hepatocellular carcinoma
Tutusaus, Anna
Càncer de fetge
Inhibidors enzimàtics
Tractament adjuvant del càncer
Liver cancer
Enzyme inhibitors
Adjuvant treatment of cancer
title_short Antiapoptotic BCL-2 proteins determine Sorafenib/regorafenib resistance and BH3-mimetic efficacy in hepatocellular carcinoma
title_full Antiapoptotic BCL-2 proteins determine Sorafenib/regorafenib resistance and BH3-mimetic efficacy in hepatocellular carcinoma
title_fullStr Antiapoptotic BCL-2 proteins determine Sorafenib/regorafenib resistance and BH3-mimetic efficacy in hepatocellular carcinoma
title_full_unstemmed Antiapoptotic BCL-2 proteins determine Sorafenib/regorafenib resistance and BH3-mimetic efficacy in hepatocellular carcinoma
title_sort Antiapoptotic BCL-2 proteins determine Sorafenib/regorafenib resistance and BH3-mimetic efficacy in hepatocellular carcinoma
dc.creator.none.fl_str_mv Tutusaus, Anna
Stefanovic, Milica
Boix i Ferrero, Loreto
Cucarull, Blanca
Zamora, Aynara
Blasco, Laura
García de Frutos, Pablo
Reig, María
Fernández-Checa Torres, José Carlos
Marí García, Montserrat
Colell Riera, Anna
Bruix Tudó, Jordi
Morales Muñoz, Albert
author Tutusaus, Anna
author_facet Tutusaus, Anna
Stefanovic, Milica
Boix i Ferrero, Loreto
Cucarull, Blanca
Zamora, Aynara
Blasco, Laura
García de Frutos, Pablo
Reig, María
Fernández-Checa Torres, José Carlos
Marí García, Montserrat
Colell Riera, Anna
Bruix Tudó, Jordi
Morales Muñoz, Albert
author_role author
author2 Stefanovic, Milica
Boix i Ferrero, Loreto
Cucarull, Blanca
Zamora, Aynara
Blasco, Laura
García de Frutos, Pablo
Reig, María
Fernández-Checa Torres, José Carlos
Marí García, Montserrat
Colell Riera, Anna
Bruix Tudó, Jordi
Morales Muñoz, Albert
author2_role author
author
author
author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv Càncer de fetge
Inhibidors enzimàtics
Tractament adjuvant del càncer
Liver cancer
Enzyme inhibitors
Adjuvant treatment of cancer
topic Càncer de fetge
Inhibidors enzimàtics
Tractament adjuvant del càncer
Liver cancer
Enzyme inhibitors
Adjuvant treatment of cancer
description Sorafenib, systemic treatment for advanced hepatocellular carcinoma (HCC), and regorafenib, novel second line treatment after sorafenib failure, have efficacy limited by evasive mechanisms of acquired-drug resistance. BCL-2 proteins participate in the response to tyrosine kinase inhibitors; however, their role in HCC therapy with sorafenib/regorafenib remains uncertain. BH3-mimetic ABT-263 (navitoclax) enhanced sorafenib activity, inducing cell death via a mitochondrial caspase-dependent mechanism, after BCL-xL/BCL-2 inhibition. Sorafenib-resistant hepatoma cells (HepG2R and Hep3BR) exhibited altered mRNA expression of BCL-2 and other anti-apoptotic family members, such as MCL-1, priming drug-resistant cancer cells to death by BH3-mimetics. ABT-263 restored sorafenib efficacy in sorafenib-resistant cell lines and HCC mouse models. Moreover, in mice xenografts from patient-derived BCLC9 cells, better tumor response to sorafenib was associated to higher changes in the BCL-2 mRNA pattern. HCC non-treated patients displayed altered BCL-2, MCL-1 and BCL-xL mRNA levels respect to adjacent non-tumoral biopsies and an increased BCL-2/MCL-1 ratio, predictive of navitoclax efficacy. Moreover, regorafenib administration also modified the BCL-2/MCL-1 ratio and navitoclax sensitized hepatoma cells to regorafenib by a mitochondrial caspase-dependent mechanism. In conclusion, sorafenib/regorafenib response is determined by BCL-2 proteins, while increased BCL-2/MCL-1 ratio in HCC sensitizes drug resistant-tumors against ABT-263 co-administration. Thus, changes in the BCL-2 profile, altered in HCC patients, could help to follow-up sorafenib efficacy, allowing patient selection for combined therapy with BH3-mimetics or early switch them to second line therapy.
publishDate 2018
dc.date.none.fl_str_mv 2018
2020
2020
2020
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv https://hdl.handle.net/2445/157937
url https://hdl.handle.net/2445/157937
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv Reproducció del document publicat a: https://doi.org/10.18632/oncotarget.24673
Oncotarget, 2018, vol. 9, num. 24, p. 16701-16717
https://doi.org/10.18632/oncotarget.24673
dc.rights.none.fl_str_mv cc-by (c) Tutusaus, Anna et al., 2018
http://creativecommons.org/licenses/by/3.0/es
info:eu-repo/semantics/openAccess
rights_invalid_str_mv cc-by (c) Tutusaus, Anna et al., 2018
http://creativecommons.org/licenses/by/3.0/es
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv 17 p.
application/pdf
dc.publisher.none.fl_str_mv Impact Journals
publisher.none.fl_str_mv Impact Journals
dc.source.none.fl_str_mv Articles publicats en revistes (Medicina)
reponame:Recercat. Dipósit de la Recerca de Catalunya
instname:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)
instname_str Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)
reponame_str Recercat. Dipósit de la Recerca de Catalunya
collection Recercat. Dipósit de la Recerca de Catalunya
repository.name.fl_str_mv
repository.mail.fl_str_mv
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score 15,812429

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