EGFR and Lyn inhibition augments regorafenib induced cell death in sorafenib resistant 3D tumor spheroid model

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 o...

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Bibliographic Details
Published in:Cellular signalling 2023-05, Vol.105, p.110608-110608, Article 110608
Main Authors: Sarıyar, Ece, Karpat, Ozum, Sezan, Sıla, Baylan, Sude Mısra, Kıpçak, Arda, Guven, Kadriye, Erdal, Esra, Fırtına Karagonlar, Zeynep
Format: Article
Language:English
Subjects:
Antineoplastic Agents - pharmacology
Antineoplastic Agents - therapeutic use
cancer spheroids
Carcinoma, Hepatocellular - drug therapy
Cell Death
Cell Line, Tumor
Drug Resistance, Neoplasm
EGFR
ErbB Receptors
Hepatocellular carcinoma
Humans
Liver Neoplasms - drug therapy
Lyn
Sorafenib - pharmacology
Sorafenib resistance
Tumor Microenvironment
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Summary: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. [Display omitted] •Sorafenib resistant spheroids also demonstrate regorafenib resistance.•Sorafenib resistant spheroids express higher levels of cancer stem cell markers such as CD24 and EpCAM.•Sorafenib resistant spheroids exhibit upregulation of key kinases such as EGFR and Lyn.•Inhibition of EGFR and Lyn kinase is efficient in inducing cell death in sorafenib resistant spheroids.
ISSN:0898-6568
1873-3913
DOI:10.1016/j.cellsig.2023.110608