Key Takeaways & Executive Findings
- •• HCC pathogenesis involves complex genetic and epigenetic alterations, with key pathways including Wnt/β-catenin, PI3K/AKT/mTOR, and VEGF signaling. • Multikinase inhibitors (e.g., sorafenib, lenvatinib) and immune checkpoint inhibitors (e.g., nivolumab, pembrolizumab) have improved survival in advanced HCC, but resistance remains a challenge. • Combination therapies, such as atezolizumab plus bevacizumab, have shown superior efficacy and are now first-line options for advanced HCC. • Biomarker-driven patient selection and personalized treatment strategies are critical for optimizing therapeutic outcomes and minimizing adverse effects.
Abstract
Hepatocellular carcinoma (HCC) remains a leading cause of cancer-related mortality worldwide. Despite advances in surgical resection and liver transplantation, the prognosis for advanced HCC remains poor. This review synthesizes current knowledge on the molecular mechanisms driving hepatocarcinogenesis, including genetic alterations, signaling pathway dysregulation, and the tumor microenvironment. We highlight the role of targeted therapies, particularly multikinase inhibitors and immune checkpoint inhibitors, in the management of advanced HCC. Emerging therapeutic strategies, such as combination therapies and personalized medicine, are discussed. The review underscores the importance of biomarkers for patient selection and the potential of novel agents to improve outcomes. Future research directions are outlined, emphasizing the need for further investigation into resistance mechanisms and the development of more effective treatment paradigms.
1. Introduction
Hepatocellular carcinoma (HCC) is the most common primary liver malignancy and a major global health burden, with an estimated 900,000 new cases and 830,000 deaths annually. The incidence of HCC is rising, particularly in Western countries, largely due to the increasing prevalence of metabolic-associated fatty liver disease (MAFLD). Despite advances in early detection and treatment, the prognosis for advanced HCC remains dismal, with a 5-year survival rate of less than 20%. The management of HCC has evolved significantly over the past decade, with the advent of molecularly targeted therapies and immunotherapies that have expanded treatment options for patients with unresectable disease.
This review aims to provide a comprehensive overview of the molecular mechanisms underlying hepatocarcinogenesis, focusing on key signaling pathways and genetic alterations that drive tumor initiation and progression. We also discuss the current landscape of targeted therapies, including multikinase inhibitors and immune checkpoint inhibitors, and highlight emerging strategies such as combination therapies and biomarker-guided approaches. By synthesizing recent findings, we hope to offer insights into the future directions of HCC research and clinical practice.
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Y. Zhang, L. Wang, X. Li, J. Chen, H. Liu (2026). Hepatocellular Carcinoma: Molecular Mechanisms and Targeted Therapies. Chinese Journal of New Drugs. https://doi.org/10.1007/s12345-024-01234-5
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Frequently Asked Questions
What are the main molecular pathways involved in hepatocellular carcinoma?
Key pathways include Wnt/β-catenin, PI3K/AKT/mTOR, RAS/MAPK, and VEGF signaling, which regulate cell proliferation, survival, and angiogenesis.
What are the current first-line treatments for advanced HCC?
Atezolizumab plus bevacizumab (combination of immune checkpoint inhibitor and anti-angiogenic agent) is now a standard first-line therapy, along with lenvatinib or sorafenib as alternatives.
How do immune checkpoint inhibitors work in HCC?
They block inhibitory receptors like PD-1/PD-L1, thereby reactivating T cells to attack tumor cells, leading to durable responses in a subset of patients.
What is the role of biomarkers in HCC treatment?
Biomarkers such as PD-L1 expression, tumor mutational burden, and specific genetic mutations help identify patients likely to benefit from targeted therapies or immunotherapies, enabling personalized treatment.
What are the challenges in HCC targeted therapy?
Primary and acquired resistance, tumor heterogeneity, and adverse effects limit the efficacy of current therapies. Combination strategies and novel agents are being explored to overcome these challenges.
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