Antitumor Effect of Lenvatinib Combined with Alisertib in Hepatocellular Carcinoma by Targeting the DNA Damage Pathway

Abstract

Background and Aim. Although a strong antitumor effect of lenvatinib has been noted for patients with unresectable hepatocellular carcinoma (HCC), its efficacy requires improvement. It is imperative to seek therapeutic strategies that combine Lenvatinib with other anticancer agents. In this study, we investigated the anticancer effect of combining lenvatinib with alisertib, aurora A kinase (AURKA) target drug, against HCC in vitro and in vivo. Methods. Immunohistochemical staining, sequencing, and genetic analysis of liver cancer tissues were performed. The antitumor efficacy of single-agent or combination treatment was measured by cell counting kit-8 assay and colony formation assays. Their antiproliferative and apoptosis activity is evaluated by cell cycle analyses and wound healing assays. The DNA-related proteins were also measured by Western blotting and immunohistochemical staining. The HepG2 xenograft model was used to detect the effects of lenvatinib-alisertib on the antitumor activity. Results. AURKA was found to be upregulated in HCC tissues (77.3%, 17/22). Combined alisertib and lenvatinib treatment significantly enhanced the inhibition of proliferation and migration in HepG2 and Hep3B cell lines compared to single-agent treatments (all P s < 0.01 ). Alisertib alone or in combination with lenvatinib demonstrated a significant increase in the percentage of super-G2 cells (lenvatinib 1 μM vs. lenvatinib 1 μM + alisertib 0.1 μM 8.84 ± 0.84 vs. 34.0 ± 1.54 , P < 0.001 ). Discontinuous spindles and missegregated chromosomes in HCC cells treated with alisertib in combination with lenvatinib were observed. We further revealed that combined treatment inhibited the expression of DNA damage pathway proteins compared to those of single-agent treatments. In nude mice, combined administration of alisertib combined with lenvatinib significantly enhanced the suppression of tumor growth and induced apoptosis (all P s < 0.01 ). Conclusions. Our findings provide evidence for the possible use of alisertib in combination with lenvatinib in the treatment of HCC for better therapeutic outcomes.

METTL16 Mediated LncRNA TIALD m6A Modification contributes to hepatocellular carcinoma metastasis via inducing AURKA lysosomal degradation

“…New drugs -lenvatinib in the frontline and regorafenib, cabozantinib, and ramucirumab in the second line -have also been demonstrated to improve clinical outcomes, but the median overall survival of these treatments still remains ~1-year, therapeutic breakthroughs are still needed. A recent study showed that alisertiblenvatinib combination contributes to the anti-tumor activity in HCC cells and xenograft tumors model 44 .…”

LncRNA TIALD contributes to hepatocellular carcinoma metastasis via inducing AURKA lysosomal degradation

“…New drugs—lenvatinib in the frontline and regorafenib, cabozantinib, and ramucirumab in the second line—have also been demonstrated to improve clinical outcomes, but the median overall survival of these treatments still remains ~1-year, therapeutic breakthroughs are still needed. A recent study showed that alisertib-lenvatinib combination contributes to the anti-tumor activity in HCC cells and xenograft tumors model [ 44 ]. The role of AURKA inhibitor in the treatment of HCC still needs more studies, including exploring more combined treatment methods and screening potential benefit patient groups, which will speed up the clinical promotion of alisertib in the treatment of HCC, and also provide more treatment options for advanced HCC.…”

The role of Aurora kinase A in hepatocellular carcinoma: Unveiling the intriguing functions of a key but still underexplored factor in liver cancer

“…81 Another study demonstrated that AURKA was significantly upregulated in 22 primary liver cancer tissues of HCC patients (77.3%, 17/22) (Table 2). 82 Given its involvement in cancer, high levels of AURKA have been linked to clinical aggressiveness, poor outcomes, unfavourable prognoses, therapeutic resistance, and increased early recurrence in HCC patients. 80,84 The patients showing high AURKA expression (n = 52) had significantly shorter overall survival (OS) and diseasefree survival rates compared to the patients with low AURKA expression (n = 86) (Table 2).…”

“…137,138 Alisertib increased the cytotoxic effects and anti-metastatic activity of lenvatinib in Hep3B (p53-deletion) and HepG2 (wild type), which may suggest that this combinatorial treatment may be effective regardless of p53 mutational status. 82 Similarly, the simultaneous inhibi- AFP, and des-gamma-carboxy-prothrombin (DCP). 145 However, the significant heterogeneity in HCC underscores the limitations of the available systems in comprehensively stratifying the patients.…”

“…In pre‐clinical studies conducted in HCC models, alisertib has been tested in combination with lenvatinib 137,138 . Alisertib increased the cytotoxic effects and anti‐metastatic activity of lenvatinib in Hep3B (p53‐deletion) and HepG2 (wild type), which may suggest that this combinatorial treatment may be effective regardless of p53 mutational status 82 . Similarly, the simultaneous inhibition of AURKA and heat shock transcription factor 1 (HSF1) with danusertib and KRIBB11, respectively, resulted in increased apoptosis of HCC cells (HepG2 and Bel‐7402) presumably through the activation of the endoplasmic reticulum stress response.…”