Application and Resistance Mechanisms of Lenvatinib in Patients with Advanced Hepatocellular Carcinoma

Abstract

Lenvatinib, a multitargeted tyrosine kinase inhibitor (TKI), is one of the preferred targeted drugs for the treatment of advanced hepatocellular carcinoma (aHCC). Since the REFLECT study showed that lenvatinib was noninferior to sorafenib in overall survival (OS), lenvatinib monotherapy has been widely used for aHCC. Moreover, lenvatinib combination therapy, especially lenvatinib combined with immune checkpoint inhibitors (ICIs), has shown more encouraging clinical results. However, drug development and comprehensive treatment have not significantly improved the prognosis, and lenvatinib resistance is often encountered in treatment. The underlying molecular mechanism of lenvatinib resistance is still unclear, and studies to solve drug resistance are ongoing. The molecular mechanisms of lenvatinib resistance in patients with aHCC include the regulation of signaling pathways, the regulation of noncoding RNAs, the impact of the immune microenvironment, tumor stem cell activation and other mechanisms. This review aims to (1) summarize the progress of lenvatinib in treating aHCC, (2) delineate the known lenvatinib resistance mechanisms of current therapy, and (3) describe the development of therapeutic methods intended to overcome these resistance mechanisms.

Strategies and Recent Advances on Improving Efficient Antitumor of Lenvatinib Based on Nanoparticle Delivery System

“…28 Furthermore, LVN can increase CD8+ T cell activity and reduce the number of myeloid-derived suppressor cells (MDSCs), thus also regulating the immune microenvironment. 18,[28][29][30] To obtain the most out of LVN, these antitumor mechanisms are adequately used and strengthened by combination therapy.…”

Protein and metabolic profiles of tyrosine kinase inhibitors co-resistant liver cancer cells

“…Recent studies have shown that epigenetics, transport processes, regulated cell death, tumor microenvironment, hypoxia and viral reactivation play a role in the production and development of sorafenib resistance in HCC ( Tang et al, 2020 ; Ladd et al, 2024 ). Lenvatinib resistance also has a similar mechanism to sorafenib resistance, including noncoding RNA regulation, tumor immune microenvironment and expansion of cancer stem cells ( Tao et al, 2023 ). In addition, the combination of immune checkpoint inhibitors (ICI) and TKIs has important therapeutic significance in the treatment of HCC ( Starzer et al, 2024 ).…”