Abstract
Hepatocellular carcinoma (HCC) is one of the major causes of cancer-related deaths worldwide. Sorafenib has been used as a first-line systemic treatment for over a decade. However, resistance to sorafenib limits patient response and presents a major hurdle during HCC treatment. Lenvatinib has been approved as a first-line systemic treatment for advanced HCC and is the first agent to achieve non-inferiority against sorafenib. Therefore, in the present study, we evaluated the inhibition efficacy of lenvatinib in sorafenib-resistant HCC cells. Only a few studies have been conducted on this topic. Two human HCC cell lines, Huh-7 and Hep-3B, were used to establish sorafenib resistance, and in vitro and in vivo studies were employed. Lenvatinib suppressed sorafenib-resistant HCC cell proliferation mainly by inducing G1 cell cycle arrest through ERK signaling. Hep-3B sorafenib-resistant cells showed partial cross-resistance to lenvatinib, possibly due to the contribution of poor autophagic responsiveness. Overall, the findings suggest that the underlying mechanism of lenvatinib in overcoming sorafenib resistance in HCC involves FGFR4-ERK signaling. Lenvatinib may be a suitable second-line therapy for unresectable HCC patients who have developed sorafenib resistance and express FGFR4.
Highlights
Hepatocellular carcinoma (HCC) is the most common primary liver cancer, with an increasing incidence over the past few decades in various populations; it is one of the major causes of cancer-related deaths worldwide [1,2]
An in vitro dosage (10 μM) of sorafenib and lenvatinib was used in the 3D spheroid culture of both wild-type and resistant cells; this showed that lenvatinib (10 μM) has an advantageous anti-proliferative effect in all cells (Huh-7, Huh-7 sorafenibresistant (Huh-7SR), Hep-3B, and Hep-3BSR) compared with sorafenib (10 μM)
Key points include the following: (i) lenvatinib suppressed sorafenib-resistant HCC cell proliferation, mainly by inducing G1 cell cycle arrest; (ii) the underlying advantage of lenvatinib in overcoming sorafenib resistance may occur through the FGFR4-ERK signaling pathway; (iii) along with HBV DNA, poor autophagic responsiveness may be a contributing factor toward partial cross-resistance; and (iv) miRNA alterations may contribute to the inhibition of sorafenib-resistant HCC cell growth and angiogenesis (Figure 9)
Summary
Hepatocellular carcinoma (HCC) is the most common primary liver cancer, with an increasing incidence over the past few decades in various populations; it is one of the major causes of cancer-related deaths worldwide [1,2]. For patients with advanced HCC, systemic therapy is available, with prolonged overall survival (OS) rates. The median survival time with sorafenib, used as a first-line systemic therapy for the past decade, was nearly 3 months longer than that with the placebo (10.7 months vs 7.9 months; hazard ratio (HR) 0.69; p < 0.001) [4]. Acquired resistance to sorafenib, which often develops within six months [5], may be associated with several factors, such as the phosphatidylinositol 3-kinase (PI3K)/Akt pathway, autophagy, epithelial-mesenchymal transition (EMT), tumor microenvironment, epigenetic regulation, microRNAs (miRNAs), and “vessel co-option”—the ability of tumors to hijack the existing vasculature in organs such as the lungs or liver, thereby limiting the need for angiogenesis [7,8]
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