EGFR and Lyn inhibition augments regorafenib induced cell death in sorafenib resistant 3D tumor spheroid model.
Cell Signal
; 105: 110608, 2023 05.
Article
em En
| MEDLINE
| ID: mdl-36693455
ABSTRACT
Hepatocellular carcinoma (HCC) is the most common primary cancer of the liver and the third most lethal malignancy worldwide. Patients with unresectable HCC receive systemic therapies, traditionally sorafenib or lenvatinib as first line therapy. Despite its poor therapeutic response and high rates of resistance, in most countries, sorafenib still remains the globally used first-line treatment for advanced HCC. Thus, preclinical models demonstrating sorafenib resistance are crucial. 3D tumor spheroid models are becoming extremely important as screening platforms for drug therapies. In this paper, we utilized sorafenib resistant Huh7 cell line and LX2 hepatic stellate cell line to establish a sorafenib resistant 3D tumor spheroid model which can be used to test second-line treatment options. Our analysis demonstrated that sorafenib resistant 3D tumor spheroids are also more resistant to regorafenib and exhibit diverse features compared to parental tumor spheroids. Sorafenib resistant spheroids had higher CD24 and EpCAM positive cancer stem cell populations. In addition, several oncogenic kinases are upregulated in the sorafenib resistant spheroids. Importantly, combined inhibition of EGFR and Lyn kinase in sorafenib resistant tumor spheroids are effective in inducing cell death. Our model proved to be an affordable and useful model to mimic drug resistant tumor microenvironment in HCC and provided novel insights into candidates for new combinational therapies.
Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Carcinoma Hepatocelular
/
Neoplasias Hepáticas
/
Antineoplásicos
Tipo de estudo:
Prognostic_studies
Limite:
Humans
Idioma:
En
Revista:
Cell Signal
Ano de publicação:
2023
Tipo de documento:
Article
País de afiliação:
Turquia
País de publicação:
ENGLAND
/
ESCOCIA
/
GB
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GREAT BRITAIN
/
INGLATERRA
/
REINO UNIDO
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SCOTLAND
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UK
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UNITED KINGDOM