BACKGROUND: Hepatocellular carcinoma (HCC) is one of the most common and lethal malignant tumours worldwide. Sorafenib (SOR) is one of the most effective single-drug systemic therapy against advanced HCC, but the identification of novel combination regimens for a continued improvement in overall survival is a big challenge. Recent studies highlighted the crucial role of focal adhesion kinase (FAK) in HCC growth. The aim of this study was to investigate the antitumor effects of three different FAK inhibitors (FAKi), alone or in combination with SOR, using in vitro and in vivo models of HCC. METHODS: The effect of PND1186, PF431396, TAE226 on cell viability was compared to SOR. Among them TAE226, emerging as the most effective FAKi, was tested alone or in combination with SOR using 2D/3D human HCC cell line cultures and HCC xenograft murine models. The mechanisms of action were assessed by gene/protein expression and imaging approaches, combined with high-throughput methods. RESULTS: TAE226 was the more effective FAKi to be combined with SOR against HCC. Combined TAE226 and SOR treatment reduced HCC growth both in vitro and in vivo by affecting tumour-promoting gene expression and inducing epigenetic changes via dysregulation of FAK nuclear interactome. We characterized a novel nuclear functional interaction between FAK and the NuRD complex. TAE226-mediated FAK depletion and SOR-promoted MAPK down-modulation caused a decrease in the nuclear amount of HDAC1/2 and a consequent increase of the histone H3 lysine 27 acetylation, thus counteracting histone H3 lysine 27 trimethylation. CONCLUSIONS: Altogether, our findings provide the first evidence that TAE226 combined with SOR efficiently reduces HCC growth in vitro and in vivo. Also, our data highlight that deep analysis of FAK nuclear interactome may lead to the identification of new promising targets for HCC therapy.

Core Facilities Bambino Gesù Children's Hospital IRCCS Rome Italy

Department of Life Health and Environmental Sciences MESVA University of L'Aquila L'Aquila Italy

Department of Paediatric Haematology Oncology and Cellular and Gene Therapy Bambino Gesù Children's Hospital IRCCS Rome Italy

Department of Translational Stem Cell Biology Research Institute of the Medical University of Varna 9002 Varna Bulgaria

Experimental Imaging Center IRCCS San Raffaele Scientific Institute 20132 Milan Italy

Francesco Balsano Foundation Rome Italy

Genetics and Rare Diseases Research Division Bambino Gesù Children's Hospital IRCCS Rome Italy

International Clinical Research Center St Anne's University Hospital Brno Czech Republic

Research Unit of Diagnostical and Management Innovations Bambino Gesù Children's Hospital IRCCS Rome Italy

Unit of Human Microbiome Multimodal Laboratory Medicine Research Area Bambino Gesù Children's Hospital IRCCS Rome Italy

Unit of Microbiomics Microbiology and Immunological Diagnostics Department of Diagnostics and Laboratory Medicine Bambino Gesù Children's Hospital IRCCS Rome Italy

Unit of Molecular Genetics of Complex Phenotypes Bambino Gesù Children's Hospital IRCCS Via S Paolo 15 00146 Rome Italy

Unit of Oncogenomic and Epigenetic IRCCS Regina Elena National Cancer Institute Rome Italy

J Exp Clin Cancer Res. 2022 Jan 27;41(1):40. doi: 10.1186/s13046-022-02247-y. PubMed

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Correction to: Focal adhesion kinase inhibitor TAE226 combined with Sorafenib slows down hepatocellular carcinoma by multiple epigenetic effects