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

Result code in IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F00159816%3A_____%2F21%3A00075007" target="_blank" >RIV/00159816:_____/21:00075007 - isvavai.cz</a>

Result on the web

<a href="https://jeccr.biomedcentral.com/track/pdf/10.1186/s13046-021-02154-8.pdf" target="_blank" >https://jeccr.biomedcentral.com/track/pdf/10.1186/s13046-021-02154-8.pdf</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.1186/s13046-021-02154-8" target="_blank" >10.1186/s13046-021-02154-8</a>

Result language

angličtina

Original language name

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

Original language description

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.

Czech name

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Czech description

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Type

J_imp - Article in a specialist periodical, which is included in the Web of Science database

CEP classification

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OECD FORD branch

30204 - Oncology

Project

<a href="/en/project/EF15_003%2F0000492" target="_blank" >EF15_003/0000492: Unveiling the molecular determinants of agingto design new therapeutics</a><br>

Continuities

P - Projekt vyzkumu a vyvoje financovany z verejnych zdroju (s odkazem do CEP)

Publication year

2021

Confidentiality

S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

Name of the periodical

JOURNAL OF EXPERIMENTAL &amp; CLINICAL CANCER RESEARCH

ISSN

1756-9966

e-ISSN

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Volume of the periodical

40

Issue of the periodical within the volume

1

Country of publishing house

GB - UNITED KINGDOM

Number of pages

19

Pages from-to

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UT code for WoS article

000719355800003

EID of the result in the Scopus database

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