Oncotarget

Research Papers:

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

Anna Tutusaus, Milica Stefanovic, Loreto Boix, Blanca Cucarull, Aynara Zamora, Laura Blasco, Pablo García de Frutos, Maria Reig, Jose C. Fernandez-Checa, Montserrat Marí, Anna Colell, Jordi Bruix and Albert Morales _

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Oncotarget. 2018; 9:16701-16717. https://doi.org/10.18632/oncotarget.24673

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Abstract

Anna Tutusaus1,2, Milica Stefanovic1, Loreto Boix3, Blanca Cucarull1,2, Aynara Zamora1, Laura Blasco1, Pablo García de Frutos1, Maria Reig3, Jose C. Fernandez-Checa1,4,5, Montserrat Marí1, Anna Colell1, Jordi Bruix3 and Albert Morales1,3

1Department of Cell Death and Proliferation, IIBB-CSIC, IDIBAPS, Barcelona, Spain

2Departament de Biomedicina, Facultat de Medicina, Universitat de Barcelona, Barcelona, Spain

3Barcelona Clinic Liver Cancer Group, Liver Unit, Hospital Clínic of Barcelona, University of Barcelona, CIBEREHD, IDIBAPS, Barcelona, Spain

4Liver Unit, Hospital Clinic, CIBEREHD, Barcelona, Spain

5Research Center for Alcoholic Liver and Pancreatic Diseases, Keck School of Medicine of the University of Southern California, Los Angeles, CA, USA

Correspondence to:

Albert Morales, email: amorales@clinic.ub.es

Keywords: liver cancer; BCL-2 family proteins; BH3-mimetics; mitochondria/apoptosis; sorafenib

Abbreviations: HCC, hepatocellular carcinoma; MMP, mitochondrial membrane potential; MOMP, mitochondrial outer membrane permeabilization; ROS, reactive oxygen species; WT, wild type

Received: November 30, 2017    Accepted: February 26, 2018    Published: March 30, 2018

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.


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