Prexasertib exerts a synergistic effect on the antitumor activity of Lenvatinib through ALOX15-mediated ferroptosis in hepatocellular carcinoma

Abstract

Hepatocellular carcinoma (HCC) is one of the most prevalent and lethal malignancies worldwide. Lenvatinib, a potent multi-receptor tyrosine kinase inhibitor approved for the treatment of advanced HCC, demonstrates limited clinical efficacy. Therefore, there is an urgent need to investigate therapeutic strategies that combine Lenvatinib with other anticancer agents. Lenvatinib induces DNA damage in tumor cells, and the inhibition of the DNA damage response (DDR) pathway is hypothesized to enhance Lenvatinib-induced tumor cell death. In this study, we initially observed that Lenvatinib upregulated phosphorylated checkpoint kinase 1 (CHK1) protein levels, a key molecule in the DDR pathway, in HCC cells. This observation prompted us to investigate the antitumor efficacy of combining Lenvatinib with Prexasertib, a novel CHK1 inhibitor. The combination demonstrated synergistic anticancer effects in HCC cells. Mechanistically, treatment with Lenvatinib and Prexasertib resulted in cell death primarily through ferroptosis. Furthermore, we found that Lenvatinib and Prexasertib cooperatively upregulated ALOX15 expression, which culminated in the induction of ferroptosis. Taken together, our findings suggest the potential application of Prexasertib in combination with Lenvatinib as a promising therapeutic strategy for HCC treatment.

Keywords: Ferroptosis; Hepatocellular carcinoma; Lenvatinib; Prexasertib; Synergistic therapy.