Hedgehog signals inhibitors reverse sorafenib resistance in patient-derived organoids models with hepatocellular carcinoma


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Siqi Wang1,Jiye Zhu1,Zhao Li1,Yang Wang1
1Department of Hepatobiliary Surgery, Peking University People’s Hospital

Abstract

Background

Hepatocellular carcinoma (HCC) is one of the most common causes of cancer death worldwide. For patients with unresectable HCC, The multikinase inhibitor sorafenib or lenvatinib are the only treatment option. However, drug resistance often occurs in most of patients. So how to improve the efficacy of drugs is an urgent problem. Patient-derived organoids (PDOs), contained kinds of primary tumor cells, are a more rational and individualized disease model to study treatment strategies, compared with cell lines and animal models. Here, we investigate whether stemness related signal inhibitors can improve the efficacy of drug treatment through constructing PDOs with HCC.

Method

The primary tumor tissues collected from HCC patients undergoing surgery at the Peking University Peoples’ Hospital, and then proceed three-dimensional cultured in vitro to form PDOs. The similarity between PDOs and originating tumors is compared by H&E staining and immunohistochemistry. The cell viability was detected after treatment with different drugs and the stem cell surface markers was detected by Immunofluorescence and Western Blotting. Evaluation of drug function by cell line were determined by clone formation and transwell assay.

Results

We established successfully PDOs with HCC and demostrated histological characteristics of the originating tumors were preserved in the PDOs. Treatment with Hedgehog signal inhibitors (GANT61) potently decreases the cell viability of PDOs, compared with signal inhibitors of Notch and Wnt and Hippo. GANT61 inhibits the expression of the stem cell marker proteins (CD44, Nanog, Oct4, Sox2) in PDOs by inhibiting the expression of the transcription factor GLI1. Furthermore, GANT61 combined with sorafenib or lenvatinib can obviously inhibit the cell viability of PDOs compared with sorafenib or lenvatinib alone. Furthermore, the combination of sorafenib and GANT61 could inhibit the clone formation and invasion ability of HCC cells significantly.

Conclusion

By inhibiting the Hedgehog signalins, GANT61 can significantly enhance the efficacy of sorafenib and lenvatinib to suppress the viability of PDOs. Therefore, while using "offensive drugs" in the clinic, we need to use stemness related drugs as "defensive drugs" to maximize the treatment efficacy.