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

Abstract 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 ove...

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Autores principales:	Ilaria Romito, Manuela Porru, Maria Rita Braghini, Luca Pompili, Nadia Panera, Annalisa Crudele, Daniela Gnani, Cristiano De Stefanis, Marco Scarsella, Silvia Pomella, Stefano Levi Mortera, Emmanuel de Billy, Adrian Libenzio Conti, Valeria Marzano, Lorenza Putignani, Manlio Vinciguerra, Clara Balsano, Anna Pastore, Rossella Rota, Marco Tartaglia, Carlo Leonetti, Anna Alisi
Formato:	article
Lenguaje:	EN
Publicado:	BMC 2021
Materias:	HCC FAK Sorafenib Epigenetic Therapy Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282
Acceso en línea:	https://doaj.org/article/4895e0e2b1b44fabbe5e18ca066750d0
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spelling	oai:doaj.org-article:4895e0e2b1b44fabbe5e18ca066750d02021-11-21T12:13:12ZFocal adhesion kinase inhibitor TAE226 combined with Sorafenib slows down hepatocellular carcinoma by multiple epigenetic effects10.1186/s13046-021-02154-81756-9966https://doaj.org/article/4895e0e2b1b44fabbe5e18ca066750d02021-11-01T00:00:00Zhttps://doi.org/10.1186/s13046-021-02154-8https://doaj.org/toc/1756-9966Abstract 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.Ilaria RomitoManuela PorruMaria Rita BraghiniLuca PompiliNadia PaneraAnnalisa CrudeleDaniela GnaniCristiano De StefanisMarco ScarsellaSilvia PomellaStefano Levi MorteraEmmanuel de BillyAdrian Libenzio ContiValeria MarzanoLorenza PutignaniManlio VinciguerraClara BalsanoAnna PastoreRossella RotaMarco TartagliaCarlo LeonettiAnna AlisiBMCarticleHCCFAKSorafenibEpigeneticTherapyNeoplasms. Tumors. Oncology. Including cancer and carcinogensRC254-282ENJournal of Experimental & Clinical Cancer Research, Vol 40, Iss 1, Pp 1-19 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	HCC FAK Sorafenib Epigenetic Therapy Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282
spellingShingle	HCC FAK Sorafenib Epigenetic Therapy Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282 Ilaria Romito Manuela Porru Maria Rita Braghini Luca Pompili Nadia Panera Annalisa Crudele Daniela Gnani Cristiano De Stefanis Marco Scarsella Silvia Pomella Stefano Levi Mortera Emmanuel de Billy Adrian Libenzio Conti Valeria Marzano Lorenza Putignani Manlio Vinciguerra Clara Balsano Anna Pastore Rossella Rota Marco Tartaglia Carlo Leonetti Anna Alisi Focal adhesion kinase inhibitor TAE226 combined with Sorafenib slows down hepatocellular carcinoma by multiple epigenetic effects
description	Abstract 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.
format	article
author	Ilaria Romito Manuela Porru Maria Rita Braghini Luca Pompili Nadia Panera Annalisa Crudele Daniela Gnani Cristiano De Stefanis Marco Scarsella Silvia Pomella Stefano Levi Mortera Emmanuel de Billy Adrian Libenzio Conti Valeria Marzano Lorenza Putignani Manlio Vinciguerra Clara Balsano Anna Pastore Rossella Rota Marco Tartaglia Carlo Leonetti Anna Alisi
author_facet	Ilaria Romito Manuela Porru Maria Rita Braghini Luca Pompili Nadia Panera Annalisa Crudele Daniela Gnani Cristiano De Stefanis Marco Scarsella Silvia Pomella Stefano Levi Mortera Emmanuel de Billy Adrian Libenzio Conti Valeria Marzano Lorenza Putignani Manlio Vinciguerra Clara Balsano Anna Pastore Rossella Rota Marco Tartaglia Carlo Leonetti Anna Alisi
author_sort	Ilaria Romito
title	Focal adhesion kinase inhibitor TAE226 combined with Sorafenib slows down hepatocellular carcinoma by multiple epigenetic effects
title_short	Focal adhesion kinase inhibitor TAE226 combined with Sorafenib slows down hepatocellular carcinoma by multiple epigenetic effects
title_full	Focal adhesion kinase inhibitor TAE226 combined with Sorafenib slows down hepatocellular carcinoma by multiple epigenetic effects
title_fullStr	Focal adhesion kinase inhibitor TAE226 combined with Sorafenib slows down hepatocellular carcinoma by multiple epigenetic effects
title_full_unstemmed	Focal adhesion kinase inhibitor TAE226 combined with Sorafenib slows down hepatocellular carcinoma by multiple epigenetic effects
title_sort	focal adhesion kinase inhibitor tae226 combined with sorafenib slows down hepatocellular carcinoma by multiple epigenetic effects
publisher	BMC
publishDate	2021
url	https://doaj.org/article/4895e0e2b1b44fabbe5e18ca066750d0
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Focal adhesion kinase inhibitor TAE226 combined with Sorafenib slows down hepatocellular carcinoma by multiple epigenetic effects

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