Synergism of the receptor tyrosine kinase Axl with ErbB receptors mediates resistance to regorafenib in hepatocellular carcinoma

Result code in IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F61989592%3A15310%2F23%3A73619928" target="_blank" >RIV/61989592:15310/23:73619928 - isvavai.cz</a>

Result on the web

<a href="https://www.frontiersin.org/journals/oncology/articles/10.3389/fonc.2023.1238883/full" target="_blank" >https://www.frontiersin.org/journals/oncology/articles/10.3389/fonc.2023.1238883/full</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.3389/fonc.2023.1238883" target="_blank" >10.3389/fonc.2023.1238883</a>

Result language

angličtina

Original language name

Synergism of the receptor tyrosine kinase Axl with ErbB receptors mediates resistance to regorafenib in hepatocellular carcinoma

Original language description

Introduction: Hepatocellular carcinoma (HCC) patients at advanced stages receive immunotherapy or treatment with tyrosine kinase inhibitors (TKIs) such as Sorafenib (Sora) or Lenvatinib in frontline as well as Regorafenib (Rego) or Cabozantinib in second-line. A major hindrance of TKI therapies is the development of resistance, which renders drug treatment futile and results in HCC progression. Methods: In this study, we addressed the impact of the receptor tyrosine kinase Axl binding to its ligand Gas6 in acquiring refractoriness to TKIs. The initial responses of Axl-positive and Axl-negative cell lines to different TKIs were assessed. Upon inducing resistance, RNA-Seq, gain- and loss-of-function studies were applied to understand and intervene with the molecular basis of refractoriness. Secretome analysis was performed to identify potential biomarkers of resistance. Results: We show that HCC cells exhibiting a mesenchymal-like phenotype were less sensitive to drug treatment, linking TKI resistance to changes in epithelial plasticity. Gas6/Axl expression and activation were upregulated in Rego-resistant HCC cells together with the induction of ErbB receptors, whereas HCC cells lacking Axl failed to stimulate ErbBs. Treatment of Rego-insensitive HCC cells with the pan-ErbB family inhibitor Afatinib rather than with Erlotinib blocking ErbB1 reduced cell viability and clonogenicity. Genetic intervention with ErbB2-4 but not ErbB1 confirmed their crucial involvement in refractoriness to Rego. Furthermore, Rego-resistant HCC cells secreted basic fibroblast growth factor (bFGF) depending on Axl expression. HCC patients treated with Sora in first-line and with Rego in second-line displayed elevated serum levels of bFGF, emphasizing bFGF as a predictive biomarker of TKI treatment. Discussion: Together, these data suggest that the inhibition of ErbBs is synthetic lethal with Rego in Axl-expressing HCC cells, showing a novel vulnerability of HCC.

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

—

Continuities

I - Institucionalni podpora na dlouhodoby koncepcni rozvoj vyzkumne organizace

Publication year

2023

Confidentiality

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

Name of the periodical

Frontiers in Oncology

ISSN

2234-943X

e-ISSN

2234-943X

Volume of the periodical

13

Issue of the periodical within the volume

SEP

Country of publishing house

CH - SWITZERLAND

Number of pages

15

Pages from-to

"1238883-1"-"1238883-15"

UT code for WoS article

001069609500001

EID of the result in the Scopus database

2-s2.0-85171886413