Evolving Therapies for Hepatocellular Carcinoma: The Role of Tyrosine Kinase Inhibitors and Combination Treatments

Based on the updated GLOBOCAN estimates in ۲۰۲۲, produced by the International Agency for Research on Cancer (IARC) and disseminated as Cancer Today on the Global Cancer Observatory, there were ۸۶۵,۲۶۹ new cases of liver cancer alongside ۷۵۷,۹۴۸ deaths worldwide. Hepatocellular Carcinoma (HCC) is the primary type of liver cancer. It often occurs in individuals with chronic or cirrhosis diseases such as HBV or HCV infections. However, HCC is usually diagnosed at an advanced stage when the treatment options are limited, leading to poor patient outcomes. Hopefully, recent advancements in cancer research have brought new hopes for HCC patients through TKI therapy. Tyrosine kinase inhibitors (TKI), inhibit the activation of signaling pathways, Which prevents tumor growth and metastasis. Since ۲۰۰۷ when the first TKI, Sorafenib, was approved by the FDA for advanced primary HCC, First-line drugs including sorafenib, Lenvatinib, and Donafenib have been approved for treating hepatocellular carcinoma (HCC). METHODS: This systematic review was conducted to highlight recent clinical studies and articles published in Frontier, PubMed, ScienceDirect, Google Scholar, and Scopus databases from ۲۰۱۱ to ۲۰۲۴. The following keywords were searched: Tyrosine Kinase inhibitors(TKI), Hepatocellular carcinoma(HCC), clinical trials for liver cancer, and Vascular endothelial growth factor receptor (VEGFR). Articles were carefully screened for relevance and inclusion, focusing on the latest advancements in TKI-based therapies for HCC. RESULTS: The articles indicate that sorafenib, the first TKI developed for HCC, was designed to target Raf kinase and block autophosphorylation of multiple tyrosine kinase receptors. While sorafenib showed initial success, it was replaced in some therapeutic methods by atezolizumab and bevacizumab combination, which led to a better outcome by preventing both angiogenesis and immune evasion. Another first-line TKI, Lenvatinib, targets VEGFR۱-۳ and PDGFRα/β. Lenvatinib is also considered a better first-line TKI than Sorafenib when treating patients, cause of its wider range of targets. Furthermore, lenvatinib demonstrated non-inferiority to sorafenib in terms of overall survival (OS) but showed better results in progression-free survival (PFS) and objective response rate (ORR). The review also highlights the efficacy of apatinib, which inhibits VEGFR۲ and prevents angiogenesis. Similarly, donafenib, which is now listed as a first-line treatment for advanced HCC, works by inhibiting Raf kinases (and blocking RTK signaling pathways. First-line TKI Combination therapies have also shown exciting clinical results. For example, the combination of sorafenib with transcatheter arterial chemoembolization (TACE) demonstrated a higher objective response rate (ORR) compared to TACE alone. Additionally, the disease control rate (DCR) was notably higher compared to the TACE-only group. CONCLUSION: In the past decade, important advancements have been made in the treatment of hepatocellular carcinoma (HCC) using tyrosine kinase inhibitors (TKIs). Although these therapies have shown improved outcomes they are not without limitations. Challenges such as drug resistance, side effects, and poor solubility continue to hinder their full therapeutic potential. To solve these problems, researchers have been focused on combination therapies to overcome these challenges. Researches are continued to optimize TKI dosing regimens, improve drug formulations to enhance solubility, and identify biomarkers for better treatment outcomes in the future.

کلیدواژه ها:

Tyrosine kinase inhibitor ، Vascular endothelial growth factor receptor ، Liver cancer ، Hepatocellular carcinoma ، Latest clinical trials of liver cancer