The median overall survival of patients with unresectable hepatocellular carcinoma (HCC) remains less than 20 months, even with the advancement of the latest drug treatments including immune checkpoint inhibitors (ICIs) and tyrosine kinase inhibitors (TKIs). ICIs are the first-line drugs; however, cases of treatment discontinuation due to immune-related adverse effects are persistent. In such cases, multiple-targeting TKIs (mTKIs) are introduced as the second-line drugs. Currently, mTKIs included four types for clinical use, such as sorafenib (SOR), lenvatinib (LEN), regorafenib (REG), and cabozantinib (CAB), all of which have antitumor effects by inducing programmed cell death (PCD) that includes apoptosis, necroptosis, and ferroptosis. The present study investigated the differences in PCD in hepatoma cell damage and cell death among various mTKIs using cytotoxicity assay, cell morphology, and PCD inhibition with human HCC lines, HepG2, and HuH-7. At clinical concentrations, SOR has induced apoptosis and necroptosis, REG has induced ferroptosis, and LEN and CAB have no direct antitumor effects. SOR or REG preadministration, when combining ICI and TKI, may enhance the antitumor effect.
AKITA et al. (2024) studied this question.