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http://hdl.handle.net/2445/157937
Title: | Antiapoptotic BCL-2 proteins determine Sorafenib/regorafenib resistance and BH3-mimetic efficacy in hepatocellular carcinoma |
Author: | 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 |
Keywords: | Càncer de fetge Inhibidors enzimàtics Tractament adjuvant del càncer Liver cancer Enzyme inhibitors Adjuvant treatment of cancer |
Issue Date: | 30-Mar-2018 |
Publisher: | Impact Journals |
Abstract: | 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. |
Note: | Reproducció del document publicat a: https://doi.org/10.18632/oncotarget.24673 |
It is part of: | Oncotarget, 2018, vol. 9, num. 24, p. 16701-16717 |
URI: | http://hdl.handle.net/2445/157937 |
Related resource: | https://doi.org/10.18632/oncotarget.24673 |
ISSN: | 1949-2553 |
Appears in Collections: | Articles publicats en revistes (Medicina) Articles publicats en revistes (IDIBAPS: Institut d'investigacions Biomèdiques August Pi i Sunyer) |
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