Small Molecule Targeted Therapy for Hepatocellular Carcinoma: From Multikinase Inhibition to Cancer Stem Cell Eradication Strategies
6 affiliations
- 1National Administration of Traditional Chinese Medicine Institutional Service Center, Beijing, China
- 2Department of Critical Care Medicine, Rongcheng Shidao People’s Hospital (Formerly Rongcheng No.2 People's Hospital), Rongcheng, China
- 3PLA Rocket Force Characteristic Medical Center, Beijing, China
- 4School of Chinese Medicine, Nanjing University of Chinese Medicine, Nanjing, China
- 5State Key Laboratory of Reproductive Medicine and Offspring Health, Clinical Center of Reproductive Medicine, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
- 6Department of Hepatology and Hematology, Shaanxi Provincial Hospital of Traditional Chinese Medicine, Xi’an, China
Abstract
Hepatocellular carcinoma (HCC) remains a leading cause of cancer-related death worldwide, posing a significant global health burden. Multikinase inhibitors (MKIs) such as sorafenib and lenvatinib are standard therapies for advanced HCC, yet most patients eventually develop drug resistance and tumor relapse, largely attributed to the presence of cancer stem cells (CSCs). These cells, which possess self-renewal capacity and intrinsic resistance to conventional treatments, drive tumor heterogeneity and recurrence. This review examines the molecular features of HCC CSCs and their regulatory networks, including Wnt/β-catenin, Phosphoinositide 3-kinase (PI3K)/Akt/Mammalian target of rapamycin (mTOR), and Notch signaling pathways. CSCs drive tyrosine kinase inhibitor (TKI) resistance through mechanisms such as Caveolin 1 (CAV1)-mediated dormancy and the CD133/Myosin heavy chain 9 (MYH9)/β-catenin axis, which sustain survival and proliferation despite targeted therapy. Recent preclinical studies have identified small molecule inhibitors targeting CSC-specific pathways and markers, including C504244, 4-MU, bestatin, OSU-CG5, and CL26, which show promise in eradicating CSC populations. Combination strategies that pair TKIs with these agents demonstrate synergistic effects, particularly when delivered via nanoparticle systems, which enhance drug bioavailability and tumor targeting. However, major barriers to clinical translation include CSC heterogeneity, microenvironmental adaptation, and the lack of reliable biomarkers for patient stratification. The shift from multikinase inhibition to CSC eradication represents a promising paradigm for transforming HCC into a more manageable disease, potentially improving long-term outcomes and reducing relapse rates.
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BibTeX
@article{wang2026small,
title = {{Small Molecule Targeted Therapy for Hepatocellular Carcinoma: From Multikinase Inhibition to Cancer Stem Cell Eradication Strategies}},
author = {Jian Wang and Chunxiu Suo and Yu Xie and Renjun Gu and Nan Lu and Xinyan Zhang and Xiaojuan Liu},
journal = {Oncology Research},
year = {2026},
month = oct,
doi = {10.32604/or.2026.087514},
url = {https://doi.org/10.32604/or.2026.087514},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Small Molecule Targeted Therapy for Hepatocellular Carcinoma: From Multikinase Inhibition to Cancer Stem Cell Eradication Strategies
AU - Jian Wang
AU - Chunxiu Suo
AU - Yu Xie
AU - Renjun Gu
AU - Nan Lu
AU - Xinyan Zhang
AU - Xiaojuan Liu
PY - 2026
DA - 2026/10/28
JO - Oncology Research
DO - 10.32604/or.2026.087514
UR - https://doi.org/10.32604/or.2026.087514
AB - Hepatocellular carcinoma (HCC) remains a leading cause of cancer-related death worldwide, posing a significant global health burden. Multikinase inhibitors (MKIs) such as sorafenib and lenvatinib are standard therapies for advanced HCC, yet most patients eventually develop drug resistance and tumor relapse, largely attributed to the presence of cancer stem cells (CSCs). These cells, which possess self-renewal capacity and intrinsic resistance to conventional treatments, drive tumor heterogeneity and recurrence. This review examines the molecular features of HCC CSCs and their regulatory networks, including Wnt/β-catenin, Phosphoinositide 3-kinase (PI3K)/Akt/Mammalian target of rapamycin (mTOR), and Notch signaling pathways. CSCs drive tyrosine kinase inhibitor (TKI) resistance through mechanisms such as Caveolin 1 (CAV1)-mediated dormancy and the CD133/Myosin heavy chain 9 (MYH9)/β-catenin axis, which sustain survival and proliferation despite targeted therapy. Recent preclinical studies have identified small molecule inhibitors targeting CSC-specific pathways and markers, including C504244, 4-MU, bestatin, OSU-CG5, and CL26, which show promise in eradicating CSC populations. Combination strategies that pair TKIs with these agents demonstrate synergistic effects, particularly when delivered via nanoparticle systems, which enhance drug bioavailability and tumor targeting. However, major barriers to clinical translation include CSC heterogeneity, microenvironmental adaptation, and the lack of reliable biomarkers for patient stratification. The shift from multikinase inhibition to CSC eradication represents a promising paradigm for transforming HCC into a more manageable disease, potentially improving long-term outcomes and reducing relapse rates.
SN - 0965-0407
SN - 1555-3906
ER -