Antiapoptotic BCL-2 proteins determine sorafenib/regorafenib resistance and BH3-mimetic efficacy in hepatocellular carcinoma
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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
Albert Morales, email: firstname.lastname@example.org
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
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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